IUPHAR/BPS Guide to Pharmacology CITE 2019-09-24T11:46:34+01:00 Dr. Simon Harding Open Journal Systems <p>This journal is designed to house citation summaries for contributions to the <a href="" target="_blank" rel="noopener">IUPHAR/BPS Guide to Pharmacology (GtoPdb) database</a>. The journal is not open to general submissions, only curators of the GtoPdb can submit to the journal. The citation summaries exist as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analysers.</p> <p>&nbsp;</p> 5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:33+01:00 Rodrigo Andrade Nicholas M. Barnes Gordon Baxter Joel Bockaert Theresa Branchek Amy Butler Marlene L. Cohen Aline Dumuis Richard M. Eglen Manfred Göthert Mark Hamblin Michel Hamon Paul R. Hartig René Hen Julie Hensler Katharine Herrick-Davis Rebecca Hills Daniel Hoyer Patrick P. A. Humphrey Klaus Peter Latté Luc Maroteaux Graeme R. Martin Derek N. Middlemiss Ewan Mylecharane John Neumaier Stephen J. Peroutka John A. Peters Bryan Roth Pramod R. Saxena Trevor Sharp Andrew Sleight Carlos M. Villalon Frank Yocca 5-HT receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on 5-HT receptors [<a href="">194</a>] and subsequently revised [<a href="">176</a>]</b>) are, with the exception of the ionotropic 5-HT<sub>3</sub> class, GPCRs where the endogenous agonist is <a href= "">5-hydroxytryptamine</a>. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT<sub>2A</sub> (non-functional), 5-HT<sub>2C</sub> (non-functional), 5-HT<sub>4</sub>, 5-HT<sub>6</sub> (non-functional) and 5-HT<sub>7</sub> receptors. Unique amongst the GPCRs, RNA editing produces 5-HT<sub>2C</sub> receptor isoforms that differ in function, such as efficiency and specificity of coupling to G<sub>q/11</sub> and also pharmacology [<a href="">40</a>, <a href="">482</a>]. Most 5-HT receptors (except 5-ht<sub>1e</sub> and 5-ht<sub>5b</sub>) play specific roles mediating functional responses in different tissues (reviewed by [<a href="">463</a>, <a href="">382</a>]). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Acetylcholine receptors (muscarinic) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:41+01:00 Nigel J. M. Birdsall Sophie Bradley David A. Brown Noel J. Buckley R.A. John Challiss Arthur Christopoulos Richard M. Eglen Frederick Ehlert Christian C. Felder Rudolf Hammer Heinz J. Kilbinger Günter Lambrecht Chris Langmead Fred Mitchelson Ernst Mutschler Neil M. Nathanson Roy D. Schwarz Andrew B. Tobin Celine Valant Jurgen Wess Muscarinic acetylcholine receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Muscarinic Acetylcholine Receptors [<a href="">45</a>]</b>) are GPCRs of the Class A, rhodopsin-like family where the endogenous agonist is <a href= "">acetylcholine</a>. In addition to the agents listed in the table, <a href= "">AC-42</a>, its structural analogues <a href= "">AC-260584</a> and <a href= "">77-LH-28-1</a>, <a href= ""><i>N</i>-desmethylclozapine</a>, <a href= "">TBPB</a> and <a href= "">LuAE51090</a> have been described as functionally selective agonists of the M<sub>1</sub> receptor subtype <em>via</em> binding in a mode distinct from that utilized by non-selective agonists [<a href="">243</a>, <a href="">242</a>, <a href="">253</a>, <a href="">155</a>, <a href="">154</a>, <a href="">181</a>, <a href="">137</a>, <a href="">11</a>, <a href="">230</a>]. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding <a href= "">gallamine</a>, <a href= "">strychnine</a> and <a href= "">brucine</a>, and the other defined by the binding of <a href= "">KT 5720</a>, <a href= "">WIN 62,577</a>, <a href= "">WIN 51,708</a> and <a href= "">staurosporine</a> [<a href="">161</a>, <a href="">162</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Adenosine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:45+01:00 Bertil B. Fredholm Bruno G. Frenguelli Rebecca Hills Adriaan P. IJzerman Kenneth A. Jacobson Karl-Norbert Klotz Joel Linden Christa E. Müller Ulrich Schwabe Gary L. Stiles Adenosine receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Adenosine Receptors [<a href="">103</a>]</b>) are activated by the endogenous ligand <a href= "">adenosine</a> (potentially <a href= "">inosine</a> also at A<sub>3</sub> receptors). Crystal structures for the antagonist-bound [<a href="">146</a>, <a href="">305</a>, <a href="">213</a>, <a href="">55</a>], agonist-bound [<a href="">362</a>, <a href="">196</a>, <a href="">198</a>] and G protein-bound A<sub>2A</sub> adenosine receptors [<a href="">43</a>] have been described. The structures of an antagonist-bound A1 receptor [<a href="">123</a>] and an adenosine-bound A1 receptor-G<sub>i</sub> complex [<a href="">80</a>] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [<a href="">51</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Adrenoceptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:49+01:00 Katrin Altosaar Poornima Balaji Richard A. Bond David B. Bylund Susanna Cotecchia Dominic Devost Van A. Doze Douglas C. Eikenburg Sarah Gora Eugénie Goupil Robert M. Graham Terry Hébert J. Paul Hieble Rebecca Hills Shahriar Kan Gayane Machkalyan Martin C. Michel Kenneth P. Minneman Sergio Parra Dianne Perez Rory Sleno Roger Summers Peter Zylbergold <b>The nomenclature of the Adrenoceptors has been agreed by the <u>NC-IUPHAR</u> Subcommittee on Adrenoceptors [<a href="">58</a>], see also [<a href="">180</a>]</b>.<br><br> <b>Adrenoceptors, &#945;<sub>1</sub></b><br>&#945;<sub>1</sub>-Adrenoceptors are activated by the endogenous agonists <a href= "">(-)-adrenaline</a> and <a href= "">(-)-noradrenaline</a>. <a href= "">phenylephrine</a>, <a href= "">methoxamine</a> and <a href= "">cirazoline</a> are agonists and <a href= "">prazosin</a> and <a href= "">cirazoline</a> antagonists considered selective for &#945;<sub>1</sub>- relative to &#945;<sub>2</sub>-adrenoceptors. <a href= "">[<sup>3</sup>H]prazosin</a> and <a href= "">[<sup>125</sup>I]HEAT</a> (BE2254) are relatively selective radioligands. <a href= "">S(+)-niguldipine</a> also has high affinity for L-type Ca<sup>2+</sup> channels. Fluorescent derivatives of <a href= "">prazosin</a> (Bodipy PLprazosin- QAPB) are used to examine cellular localisation of &#945;<sub>1</sub>-adrenoceptors. Selective &#945;<sub>1</sub>-adrenoceptor agonists are used as nasal decongestants; antagonists to treat hypertension (<a href= "">doxazosin</a>, <a href= "">prazosin</a>) and benign prostatic hyperplasia (<a href= "">alfuzosin</a>, <a href= "">tamsulosin</a>). The &#945;<sub>1</sub>- and &#946;<sub>2</sub>-adrenoceptor antagonist <a href= "">carvedilol</a> is used to treat congestive heart failure, although the contribution of &#945;<sub>1</sub>-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;<sub>1</sub>-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension and extrapyramidal effects.<br><br><b>Adrenoceptors, &#945;<sub>2</sub></b> <br>&#945;<sub>2</sub>-Adrenoceptors are activated by <a href= "">(-)-adrenaline</a> and with lower potency by <a href= "">(-)-noradrenaline</a>. <a href= "">brimonidine</a> and <a href= "">talipexole</a> are agonists and <a href= "">rauwolscine</a> and <a href= "">yohimbine</a> antagonists selective for &#945;<sub>2</sub>- relative to &#945;<sub>1</sub>-adrenoceptors. <a href= "">[<sup>3</sup>H]rauwolscine</a>, <a href= "">[<sup>3</sup>H]brimonidine</a> and <a href= "">[<sup>3</sup>H]RX821002</a> are relatively selective radioligands. There is species variation in the pharmacology of the &#945;<sub>2A</sub>-adrenoceptor. Multiple mutations of &#945;<sub>2</sub>-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;<sub>2</sub>-adrenoceptors regulate many functions in the nervous system. The &#945;<sub>2</sub>-adrenoceptor agonists <a href= "">clonidine</a>, <a href= "">guanabenz</a> and <a href= "">brimonidine</a> affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. <a href= "">clonidine</a> is an anti-hypertensive and counteracts opioid withdrawal. <a href= "">dexmedetomidine</a> (also <a href= "">xylazine</a>) is used as a sedative and analgesic in human and veterinary medicine with sympatholytic and anxiolytic properties. The &#945;<sub>2</sub>-adrenoceptor antagonist <a href= "">yohimbine</a> has been used to treat erectile dysfunction and <a href= "">mirtazapine</a> as an anti-depressant. The &#945;<sub>2B</sub> subtype appears to be involved in neurotransmission in the spinal cord and &#945;<sub>2C</sub> in regulating catecholamine release from adrenal chromaffin cells.<br><br><b>Adrenoceptors, &#946;</b><br>&#946;-Adrenoceptors are activated by the endogenous agonists <a href= "">(-)-adrenaline</a> and <a href= "">(-)-noradrenaline</a>. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;<sub>1</sub>- and &#945;<sub>2</sub>-adrenoceptors, while <a href= "">propranolol</a> (p<i>K</i><sub>i</sub> 8.2-9.2) and <a href= "">cyanopindolol</a> (p<i>K</i><sub>i</sub> 10.0-11.0) are relatively &#946;<sub>1</sub> and &#946;<sub>2</sub> adrenoceptor-selective antagonists. <a href= "">(-)-noradrenaline</a>, <a href= "">xamoterol</a> and <a href= "">(-)-Ro 363</a> show selectivity for &#946;<sub>1</sub>- relative to &#946;<sub>2</sub>-adrenoceptors. Pharmacological differences exist between human and mouse &#946;<sub>3</sub>-adrenoceptors, and the 'rodent selective' agonists <a href= "">BRL 37344</a> and <a href= "">CL316243</a> have low efficacy at the human &#946;<sub>3</sub>-adrenoceptor whereas <a href= "">CGP 12177</a> and <a href= "">L 755507</a> activate human &#946;<sub>3</sub>-adrenoceptors [88]. &#946;<sub>3</sub>-Adrenoceptors are resistant to blockade by <a href= "">propranolol</a>, but can be blocked by high concentrations of <a href= "">bupranolol</a>. <a href= "">SR59230A</a> has reasonably high affinity at &#946;<sub>3</sub>-adrenoceptors, but does not discriminate well between the three &#946;- subtypes whereas <a href= "">L 755507</a> is more selective. [<sup>125</sup>I]-<a href= "">cyanopindolol</a>, [<sup>125</sup>I]-hydroxy benzylpindolol and [<sup>3</sup>H]-<a href= "">alprenolol</a> are high affinity radioligands that label &#946;<sub>1</sub>- and &#946;<sub>2</sub>- adrenoceptors and &#946;<sub>3</sub>-adrenoceptors can be labelled with higher concentrations (nM) of [<sup>125</sup>I]-<a href= "">cyanopindolol</a> together with &#946;<sub>1</sub>- and &#946;<sub>2</sub>-adrenoceptor antagonists. [<sup>3</sup>H]-L-748337 is a &#946;<sub>3</sub>-selective radioligand [<a href="">474</a>]. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;<sub>1</sub>-adrenoceptor agonists (<a href= "">denopamine</a>, <a href= "">dobutamine</a>) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;<sub>1</sub>-Adrenoceptor-preferring antagonists are used to treat hypertension (<a href= "">atenolol</a>, <a href= "">betaxolol</a>, <a href= "">bisoprolol</a>, <a href= "">metoprolol</a> and <a href= "">nebivolol</a>), cardiac arrhythmias (<a href= "">atenolol</a>, bisoprolol, <a href= "">esmolol</a>) and cardiac failure (<a href= "">metoprolol</a>, nebivolol). Cardiac failure is also treated with carvedilol that blocks &#946;<sub>1</sub>- and &#946;<sub>2</sub>-adrenoceptors, as well as &#945;<sub>1</sub>-adrenoceptors. Short (<a href= "">salbutamol</a>, <a href= "">terbutaline</a>) and long (<a href= "">formoterol</a>, <a href= "">salmeterol</a>) acting &#946;<sub>2</sub>-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (<a href= "">propranolol</a>) block both &#946;<sub>1</sub>- and &#946;<sub>2</sub>-adrenoceptors and there are no &#946;<sub>2</sub>-adrenoceptor-selective antagonists used therapeutically. The &#946;<sub>3</sub>-adrenoceptor agonist <a href= "">mirabegron</a> is used to control overactive bladder syndrome. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Complement peptide receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:54+01:00 Antonia Cianciulli Liam Coulthard Owen Hawksworth John D. Lee Vincenzo Mitolo Peter Monk Maria A. Panaro Trent M. Woodruff Complement peptide receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Complement peptide receptors [<a href="">98</a>]</b>) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides <a href= "">C3a</a> and <a href= "">C5a</a>, generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3aR and C5aR), causing cell activation and triggering cellular degranulation that contributes to the local inflammation. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Angiotensin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:19:56+01:00 Wayne Alexander Kenneth E. Bernstein Kevin J. Catt Marc de Gasparo Khuraijam Dhanachandra Singh Satoru Eguchi Emanuel Escher Theodore L. Goodfriend Mastgugu Horiuchi László Hunyady Ahsan Husain Tadashi Inagami Sadashiva Karnik Jacqueline Kemp Walter G. Thomas Pieter B. M. W. M. Timmermans Kalyan Tirupula Hamiyet Unal Thomas Unger Patrick Vanderheyden The actions of <a href= "">angiotensin II</a> (Ang II) are mediated by AT<sub>1</sub> and AT<sub>2</sub> receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Angiotensin receptors [<a href="">61</a>, <a href="">152</a>]</b>), which have around 30% sequence similarity. The decapeptide <a href= "">angiotensin I</a>, the octapeptide <a href= "">angiotensin II</a> and the heptapeptide <a href= "">angiotensin III</a> are endogenous ligands. <a href= "">losartan</a>, <a href= "">candesartan</a>, <a href= "">telmisartan</a>, etc. are clinically used AT<sub>1</sub> receptor blockers. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Apelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:02+01:00 Anthony P. Davenport Matthias Kleinz Tom Lloyd Williams Robyn Macrae Janet J. Maguire Duuamene Nyimanu Peiran Yang The apelin receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the apelin receptor [<a href="">68</a>]</b>) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. <a href= "">apelin-36</a>, <a href= "">apelin-13</a> and <a href= "">[Pyr<sup>1</sup>]apelin-13</a> are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (<a href="!/hgnc_id/HGNC:16665"><i>APLN</i></a>, <a href="">Q9ULZ1</a>) by a so far unidentified enzymatic pathway [<a href="">80</a>]. A second family of peptides discovered independently and named Elabela [<a href="">11</a>] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [<a href="">87</a>, <a href="">67</a>]. Structure-activity relationship Elabela analogues have been described [<a href="">61</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Bile acid receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:03+01:00 Tom I. Bonner Anthony P. Davenport Rebecca Hills Janet J. Maguire Edward Rosser The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of <a href= "">cholesterol</a>. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Bombesin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:04+01:00 Jim Battey Richard V. Benya Robert T. Jensen Terry W. Moody Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB<sub>1</sub>, BB<sub>2</sub>, BB<sub>3</sub> (<b>nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, [<a href="">109</a>]</b>). BB<sub>1</sub> and BB<sub>2</sub> are activated by the endogenous ligands <a href= "">gastrin-releasing peptide</a> (GRP), <a href= "">neuromedin B</a> (NMB) and <a href= "">GRP-(18-27)</a>. <a href= "">bombesin</a> is a tetradecapeptide, originally derived from amphibians. The three Bn receptor subtypes couple primarily to the G<sub>q/11</sub> and G<sub>12/13</sub> family of G proteins [<a href="">109</a>]. Each of these receptors is widely distributed in the CNS and peripheral tissues [<a href="">73</a>, <a href="">109</a>, <a href="">236</a>, <a href="">265</a>, <a href="">226</a>, <a href="">348</a>]. Activation of BB<sub>1</sub> and BB<sub>2</sub> receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm and mediation of pruritus [112, 113, <a href="">109</a>, 115, 116, <a href="">155</a>, <a href="">189</a>, <a href="">236</a>]. A physiological role for the BB<sub>3</sub> receptor has yet to be fully defined although recently studies suggest an important role in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [<a href="">73</a>, <a href="">157</a>, <a href="">203</a>, <a href="">332</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Bradykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:09+01:00 Joseph Coulson Réjean Couture Alexander Faussner Fernand Gobeil Jr Fredrik Leeb-Lundberg Francois Marceau Werner Muller-Esterl Doug Pettibone Bruce Zuraw Bradykinin (or kinin) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Bradykinin (kinin) Receptors [<a href="">76</a>]</b>) are activated by the endogenous peptides <a href= "">bradykinin</a> (BK), <a href= "">[des-Arg<sup>9</sup>]bradykinin</a>, Lys-BK (<a href= "">kallidin</a>), <a href= "">[des-Arg<sup>10</sup>]kallidin</a>, [Phospho-Ser<sup>6</sup>]-Bradykinin, <a href= "">T-kinin</a> (Ile-Ser-BK), <a href= "">[Hyp<sup>3</sup>]bradykinin</a> and <a href= "">Lys-[Hyp<sup>3</sup>]-bradykinin</a>. Variation in pharmacology and activity of B<sub>1</sub> and B<sub>2</sub> receptor antagonists at species orthologs has been documented. <a href= "">icatibant</a> (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Calcitonin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:11+01:00 Debbie Hay David R. Poyner Christopher S. Walker This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on CGRP, AM, AMY, and CT receptors [<a href="">122</a>, <a href="">67</a>]</b>) are generated by the genes <a href="!/hgnc_id/HGNC:1440"><i>CALCR</i></a> (which codes for the CT receptor) and <a href="!/hgnc_id/HGNC:16709"><i>CALCRL</i></a> (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of <i>ca.</i> 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CT receptor; these in turn produce variants of the AMY receptor [<a href="">122</a>], some of which can be potently activated by CGRP. The endogenous agonists are the peptides <a href= "">calcitonin</a>, <a href= "">&#945;-CGRP</a> (formerly known as CGRP-I), <a href= "">&#946;-CGRP</a> (formerly known as CGRP-II), <a href= "">amylin</a> (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), <a href= "">adrenomedullin</a> and <a href= "">adrenomedullin 2/intermedin</a>. There are species differences in peptide sequences, particularly for the CTs. <a href= "">CTR-stimulating peptide</a> (CRSP) is another member of the family with selectivity for the CT receptor but it is not expressed in humans [<a href="">87</a>]. <a href= "">olcegepant</a> (also known as BIBN4096BS, <em>p</em>Ki~10.5) and <a href= "">telcagepant</a> (also known as MK0974, <em>p</em>Ki~9) are the most selective antagonists available, showing selectivity for CGRP receptors, with a particular preference for those of primate origin. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Calcium-sensing receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:13+01:00 Daniel Bikle Hans Bräuner-Osborne Edward M. Brown Wenhan Chang Arthur Conigrave Fadil Hannan Katie Leach Daniela Riccardi Dolores Shoback Donald T. Ward Polina Yarova The calcium-sensing receptor (CaS, <b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">44</a>]</b>) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [<a href="">74</a>]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [<a href="">14</a>, <a href="">106</a>], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [<a href="">34</a>, <a href="">44</a>, <a href="">58</a>, <a href="">104</a>, <a href="">105</a>]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [<a href="">143</a>, <a href="">51</a>]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [<a href="">17</a>] or decreased extracellular ionic strength [<a href="">105</a>]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Cannabinoid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:16+01:00 Mary Abood Stephen P.H. Alexander Francis Barth Tom I. Bonner Heather Bradshaw Guy Cabral Pierre Casellas Ben F. Cravatt William A. Devane Vincenzo Di Marzo Maurice R. Elphick Christian C. Felder Peter Greasley Miles Herkenham Allyn C. Howlett George Kunos Ken Mackie Raphael Mechoulam Roger G. Pertwee Ruth A. Ross Cannabinoid receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Cannabinoid Receptors [<a href="">107</a>]</b>) are activated by endogenous ligands that include N-arachidonoylethanolamine (<a href= "">anandamide</a>), <a href= "">N-homo-&#947;-linolenoylethanolamine</a>, <a href= "">N-docosatetra-7,10,13,16-enoylethanolamine</a> and <a href= "">2-arachidonoylglycerol</a>. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [<a href="">4</a>].<br><br>There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB<sub>1</sub> and CB<sub>2</sub> receptors [<a href="">104</a>]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are <a href= "">nabilone</a> (Cesamet&#174;), a synthetic CB<sub>1</sub>/CB<sub>2</sub> receptor agonist, and synthetic <a href= "">&#916;<sup>9</sup>-tetrahydrocannabinol</a> (Marinol&#174;; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex&#174;, contains mainly <a href= "">&#916;<sup>9</sup>-tetrahydrocannabinol</a> and <a href= "">cannabidiol</a>, both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Chemokine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:18+01:00 Francoise Bachelerie Adit Ben-Baruch Israel F. Charo Christophe Combadiere Reinhold Förster Joshua M. Farber Gerard J. Graham Rebecca Hills Richard Horuk Massimo Locati Andrew D. Luster Alberto Mantovani Kouji Matsushima Amy E. Monaghan Georgios L. Moschovakis Philip M. Murphy Robert J. B. Nibbs Hisayuki Nomiyama Joost J. Oppenheim Christine A. Power Amanda E. I. Proudfoot Mette M. Rosenkilde Antal Rot Silvano Sozzani Marcus Thelen Osamu Yoshie Albert Zlotnik Chemokine receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Chemokine Receptors [<a href="">417</a>, <a href="">416</a>, <a href="">31</a>]</b>) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibiotics, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and "Atypical chemokine receptors", which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [<a href="">31</a>].<br><br>Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as &#946;-chemokines; <i>n</i>= 28), CXC (also known as <em>&#945;</em>-chemokines; <i>n</i>= 17) and CX3C (<i>n</i>= 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (<i>n</i>= 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [<a href="">32</a>]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [<a href="">657</a>] and aliases. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Cholecystokinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:27+01:00 Margery Beinfeld Quan Chen Fan Gao Roger A. Liddle Laurence J. Miller Jens Rehfeld Cholecystokinin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on CCK receptors [<a href="">89</a>]</b>) are activated by the endogenous peptides cholecystokinin-8 (<a href= "">CCK-8</a>), <a href= "">CCK-33</a>, <a href= "">CCK-58</a> and gastrin (<a href= "">gastrin-17</a>). There are only two distinct subtypes of CCK receptors, CCK<sub>1</sub> and CCK<sub>2</sub> receptors [<a href="">63</a>, <a href="">123</a>], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK<sub>1</sub> receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK<sub>2</sub> receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Class A Orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:29+01:00 Stephen P.H. Alexander Jim Battey Helen E. Benson Richard V. Benya Tom I. Bonner Anthony P. Davenport Satoru Eguchi Anthony Harmar Nick Holliday Robert T. Jensen Sadashiva Karnik Evi Kostenis Wen Chiy Liew Amy E. Monaghan Chido Mpamhanga Richard Neubig Adam J. Pawson Jean-Philippe Pin Joanna L. Sharman Michael Spedding Eliot Spindel Leigh Stoddart Laura Storjohann Walter G. Thomas Kalyan Tirupula Patrick Vanderheyden Table 1 lists a number of putative GPCRs identified by <b> <u>NC-IUPHAR</u> [<a href="">191</a>]</b>, for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [<a href="">148</a>]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.<br><br><b>Table 1</b>: Class A orphan GPCRs with putative endogenous ligands<br> <table class="tableizer-table"> <tr><td><a href="#83"><i>GPR3</i></a></td><td><a href="#84"><i>GPR4</i></a></td><td><a href="#85"><i>GPR6</i></a></td><td><a href="#86"><i>GPR12</i></a></td><td><a href="#87"><i>GPR15</i></a></td><td><a href="#88"><i>GPR17</i></a></td><td><a href="#91"><i>GPR20</i></a></td></tr> <tr><td><a href="#93"><i>GPR22</i></a></td><td><a href="#96"><i>GPR26</i></a></td><td><a href="#98"><i>GPR31</i></a></td><td><a href="#101"><i>GPR34</i></a></td><td><a href="#102"><i>GPR35</i></a></td><td><a href="#103"><i>GPR37</i></a></td><td><a href="#105"><i>GPR39</i></a></td></tr> <tr><td><a href="#107"><i>GPR50</i></a></td><td><a href="#112"><i>GPR63</i></a></td><td><a href="#113"><i>GRP65</i></a></td><td><a href="#114"><i>GPR68</i></a></td><td><a href="#115"><i>GPR75</i></a></td><td><a href="#120"><i>GPR84</i></a></td><td><a href="#122"><i>GPR87</i></a></td></tr> <tr><td><a href="#123"><i>GPR88</i></a></td><td><a href="#128"><i>GPR132</i></a></td><td><a href="#135"><i>GPR149</i></a></td><td><a href="#141"><i>GPR161</i></a></td><td><a href="#81"><i>GPR183</i></a></td><td><a href="#147"><i>LGR4</i></a></td><td><a href="#148"><i>LGR5</i></a></td></tr> <tr><td><a href="#149"><i>LGR6</i></a></td><td><a href="#150"><i>MAS1</i></a></td><td><a href="#152"><i>MRGPRD</i></a></td><td><a href="#156"><i>MRGPRX1</i></a></td><td><a href="#157"><i>MRGPRX2</i></a></td><td><a href="#165"><i>P2RY10</i></a></td><td><a href="#167"><i>TAAR2</i></a></td></tr> </table> <br/>In addition the orphan receptors <a href="#89"><i>GPR18</i></a>, <a href="#109"><i>GPR55</i></a> and <a href="#126"><i>GPR119</i></a> which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (<a href="FamilyDisplayForward?familyId=114">GPR18, GPR55 and GPR119</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Adhesion Class GPCRs (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:36+01:00 Demet Arac-Ozkan Gabriela Aust Tom I. Bonner Heike Cappallo-Obermann Caroline Formstone Jörg Hamann Breanne Harty Henrike Heyne Christiane Kirchhoff Barbara Knapp Arunkumar Krishnan Tobias Langenhan Diana Le Duc Hsi-Hsien Lin David C. Martinelli Kelly Monk Xianhua Piao Simone Prömel Torsten Schöneberg Helgi Schiöth Kathleen Singer Martin Stacey Yuri Ushkaryov Uwe Wolfrum Lei Xu Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [<a href="">8</a>] containing a GPCR proteolytic site. The N-terminus often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [<a href="">82</a>, <a href="">332</a>]. Several receptors have been suggested to function as mechanosensors [<a href="">254</a>, <a href="">234</a>, <a href="">315</a>, <a href="">32</a>]. <b>The nomenclature of these receptors was revised in 2015 as recommended by <u>NC-IUPHAR</u> and the <u>Adhesion GPCR Consortium</u></b> [<a href="">100</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Class C Orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:41+01:00 Daniel Bikle Hans Bräuner-Osborne Edward M. Brown Arthur Conigrave Dolores Shoback This set contains class C 'orphan' G protein coupled receptors where the endogenous ligand(s) is not known. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Corticotropin-releasing factor receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:42+01:00 Frank M. Dautzenberg, Dimitri E. Grigoriadis Richard L. Hauger Victoria B. Risbrough Thomas Steckler Wylie W. Vale Rita J. Valentino Corticotropin-releasing factor (CRF, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Corticotropin-releasing Factor Receptors [<a href="">30</a>]</b>) receptors are activated by the endogenous peptides <a href= "">corticotrophin-releasing hormone</a>, a 41 amino-acid peptide, <a href= "">urocortin 1</a>, 40 amino-acids, <a href= "">urocortin 2</a>, 38 amino-acids and <a href= "">urocortin 3</a>, 38 amino-acids. CRF<sub>1</sub> and CRF<sub>2</sub> receptors are activated non-selectively by CRH and UCN. CRF<sub>2</sub> receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [<sup>125</sup>I]Tyr<sup>0</sup>-CRF or <a href= "">[<sup>125</sup>I]Tyr<sup>0</sup>-sauvagine</a> with <i>K</i><sub>d</sub> values of 0.1-0.4 nM. CRF<sub>1</sub> and CRF<sub>2</sub> receptors are non-selectively antagonized by <a href= "">&#945;-helical CRF</a>, <a href= "">D-Phe-CRF-(12-41)</a> and <a href= "">astressin</a>. CRF<sub>1</sub> receptors are selectively antagonized by small molecules <a href= "">NBI27914</a>, <a href= "">R121919</a>, <a href= "">antalarmin</a>, <a href= "">CP 154,526</a>, <a href= "">CP 376,395</a>. CRF<sub>2</sub> receptors are selectively antagonized by <a href= "">antisauvagine</a> and astressin 2B. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Dopamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:20:43+01:00 Jean-Martin Beaulieu Emiliana Borrelli Arvid Carlsson Marc G. Caron Olivier Civelli Stefano Espinoza Gilberto Fisone Raul R. Gainetdinov David K. Grandy John W. Kebabian Saloman Z. Langer Maria Cristina Missale Kim A. Neve Bernard Scatton Jean-Charles Schwartz Goran Sedvall Philip Seeman David R. Sibley Pierre Sokoloff Pierre F. Spano Hubert H. M. Van Tol Dopamine receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Dopamine Receptors [363]</b>) are commonly divided into D<sub>1</sub>-like (D<sub>1</sub> and D<sub>5</sub>) and D<sub>2</sub>-like (D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub>) families, where the endogenous agonist is <a href= "">dopamine</a>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Endothelin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:25+01:00 Pedro D'Orléans-Juste Anthony P. Davenport Théophile Godfraind Janet J. Maguire Eliot H. Ohlstein Robert R. Ruffolo Endothelin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Endothelin Receptors [<a href="">24</a>]</b>) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (<a href= "">endothelin-1</a>, <a href= "">endothelin-2</a> and <a href= "">endothelin-3</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## G protein-coupled estrogen receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:27+01:00 Edward Filardo Richard Neubig Eric R. Prossnitz The G protein-coupled estrogen receptor (GPER, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the G protein-coupled estrogen receptor [<a href="">24</a>]</b>) was identified following observations of estrogen-evoked <a href= "">cyclic AMP</a> signalling in breast cancer cells [<a href="">2</a>], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [<a href="">5</a>]. There are observations of both cell-surface and intracellular expression of the GPER receptor [<a href="">27</a>, <a href="">32</a>]. Selective agonist/ antagonists for GPER have been characterized [<a href="">24</a>]. Antagonists of the nuclear estrogen receptor, such as <a href= "">fulvestrant</a> [<a href="">10</a>], <a href= "">tamoxifen</a> [<a href="">27</a>, <a href="">32</a>] and <a href= "">raloxifene</a> [<a href="">23</a>], as well as the flavonoid 'phytoestrogens' <a href= "">genistein</a> and <a href= "">quercetin</a> [<a href="">16</a>], are agonists of GPER. A complete review of GPER pharmacology has been recently published [<a href="">24</a>]. The roles of GPER in physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [<a href="">24</a>, <a href="">25</a>, <a href="">18</a>, <a href="">15</a>, <a href="">8</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Formylpeptide receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:28+01:00 Magnus Bäck François Boulay Nan Chiang NCHIANG@PARTNERS.ORG Sven-Erik Dahlén Claes Dahlgren Jeffrey Drazen Jilly F. Evans Craig Gerard Philip M. Murphy Marc Parmentier Mark Quinn G. Enrico Rovati Charles N. Serhan Takao Shimizu Ji Ming Wang Richard D. Ye Takehiko Yokomizo The <a href="">formylpeptide receptors</a> (<b>nomenclature agreed by the <u>NC-IUPHAR</u> Subcommittee on the formylpeptide receptor family [<a href="">185</a>]</b>) respond to exogenous ligands such as the bacterial product <a href= "">fMet-Leu-Phe</a> (fMLP) and endogenous ligands such as <a href= "">annexin I</a> , <a href= "">cathepsin G</a>, amyloid &#946;42, serum amyloid A and <a href= "">spinorphin</a>, derived from <a href= "">&#946;-haemoglobin</a>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Free fatty acid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:30+01:00 Celia Briscoe Andrew Brown Nick Holliday Stephen Jenkinson Graeme Milligan Amy E. Monaghan Leigh Stoddart Free fatty acid receptors (FFA, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on free fatty acid receptors [<a href="">111</a>, <a href="">24</a>]</b>) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (<a href= "">myristic acid</a>), C16:0 (<a href= "">palmitic acid</a>), C18:1 (<a href= "">oleic acid</a>), C18:2 (<a href= "">linoleic acid</a>), C18:3, (<a href= "">&#945;-linolenic acid</a>), C20:4 (<a href= "">arachidonic acid</a>), C20:5,n-3 (<a href= "">EPA</a>) and C22:6,n-3 (<a href= "">docosahexaenoic acid</a>)) activate FFA1 [<a href="">8</a>, <a href="">50</a>, <a href="">60</a>] and FFA4 receptors [<a href="">41</a>, <a href="">48</a>, <a href="">90</a>], while short chain fatty acids (C2 (<a href= "">acetic acid</a>), C3 (<a href= "">propanoic acid</a>), C4 (<a href= "">butyric acid</a>) and C5 (<a href= "">pentanoic acid</a>)) activate FFA2 [<a href="">9</a>, <a href="">62</a>, <a href="">86</a>] and FFA3 [<a href="">9</a>, <a href="">62</a>] receptors. The crystal structure for agonist bound FFA1 has been described [<a href="">108</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Class Frizzled GPCRs (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:33+01:00 Elisa Arthofer Jacomijn Dijksterhuis Belma Hot Pawe&lstrok; Kozielewicz Matthias Lauth Jessica Olofsson Julian Petersen Tilman Polonio Gunnar Schulte Katerina Strakova Jana Valnohova Shane Wright Receptors of the Class Frizzled (FZD, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on the Class Frizzled GPCRs [<a href="">156</a>]</b>), are GPCRs originally identified in <i>Drosophila</i> [<a href="">17</a>], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [<a href="">156</a>]. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator <a href= "">&#946;-catenin</a> or being &#946;-catenin-independent (often referred to as canonical <i>vs.</i> non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors <a href="!/hgnc_id/HGNC:6697"><i>LRP5</i></a> (<a href="">O75197</a>) and <a href="!/hgnc_id/HGNC:6698"><i>LRP6</i></a> (<a href="">O75581</a>), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of &#946;-catenin and subsequently its translocation to the nucleus. &#946;-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. &#946;-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [<a href="">28</a>, <a href="">159</a>, <a href="">135</a>], the elevation of intracellular calcium [<a href="">164</a>], activation of cGMP-specific PDE6 [<a href="">2</a>] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [<a href="">48</a>]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal <i>via</i> heterotrimeric G proteins [<a href="">213</a>, <a href="">214</a>]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. Importantly, FZDs exist in at least two distinct conformational states that regulate the pathway selection [<a href="">214</a>]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [<a href="">19</a>], as well as for &#946;-catenin-dependent [<a href="">12</a>] and -independent [<a href="">80</a>, <a href="">13</a>] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), <a href= "">Wnt-inhibitory factor</a> (WIF), <a href= "">sclerostin</a> or Dickkopf (DKK)), as well as modulatory (co)-receptors with <a href="FamilyDisplayForward?familyId=304#Type XV RTKs: RYK">Ryk</a>, <a href="FamilyDisplayForward?familyId=304#Type VIII RTKs: ROR1">ROR1</a>, <a href="FamilyDisplayForward?familyId=304#Type VIII RTKs: ROR2">ROR2</a> and Kremen, which may also function as independent signalling proteins. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## GABA<sub>B</sub> receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:36+01:00 Bernhard Bettler Norman G. Bowery John F. Cryan Sam J. Enna David H. Farb Wolfgang Foestl Klemens Kaupmann Jean-Philippe Pin Functional GABA<sub>B</sub> receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on GABA<sub>B</sub> receptors [<a href="">11</a>, <a href="">72</a>]</b>) are formed from the heterodimerization of two similar 7TM subunits termed GABA<sub>B1</sub> and GABA<sub>B2</sub> [<a href="">11</a>, <a href="">71</a>, <a href="">28</a>, <a href="">72</a>, <a href="">85</a>]. GABA<sub>B</sub> receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABA<sub>B1</sub> subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. Co-expression of GABA<sub>B1</sub> and GABA<sub>B2</sub> subunits allows transport of GABA<sub>B1</sub> to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca<sup>2+</sup> channels (Ca<sub>v</sub>2.1, Ca<sub>v</sub>2.2), or inwardly rectifying potassium channels (Kir3) [<a href="">12</a>, <a href="">11</a>, <a href="">5</a>]. The GABA<sub>B1</sub> subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA<sub>B2</sub> subunit mediates G protein-coupled signalling [<a href="">11</a>, <a href="">71</a>, <a href="">40</a>, <a href="">39</a>]. The two subunits interact by direct allosteric coupling [<a href="">63</a>], such that GABA<sub>B2</sub> increases the affinity of GABA<sub>B1</sub> for agonists and reciprocally GABA<sub>B1</sub> facilitates the coupling of GABA<sub>B2</sub> to G proteins [<a href="">71</a>, <a href="">54</a>, <a href="">39</a>]. GABA<sub>B1</sub> and GABA<sub>B2</sub> subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between &#945;-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABA<sub>B1</sub> subunit but other domains of the proteins also contribute to their heteromerization [<a href="">5</a>, <a href="">71</a>, <a href="">15</a>]. Recent evidence indicates that higher order assemblies of GABA<sub>B </sub>receptor comprising dimers of heterodimers occur in recombinant expression systems and <em>in vivo</em> and that such complexes exhibit negative functional cooperativity between heterodimers [<a href="">70</a>, <a href="">22</a>]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABA<sub>B2</sub> subunit to impart altered signalling kinetics and agonist potency to the receptor complex [<a href="">84</a>, <a href="">3</a>, <a href="">79</a>] and are reviewed by [<a href="">73</a>]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [Schwenk et al., 2016, Nature Neuroscience 19(2): 233-42] and reviewed by [<a href="">69</a>]. Four isoforms of the human GABA<sub>B1</sub> subunit have been cloned. The predominant GABA<sub>B1a</sub> and GABA<sub>B1b</sub> isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABA<sub>B1a</sub>-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABA<sub>B1b</sub>-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [<a href="">75</a>, <a href="">89</a>]. Only the 1a and 1b variants are identified as components of native receptors [<a href="">11</a>]. Additional GABA<sub>B1</sub> subunit isoforms have been described in rodents and humans [<a href="">55</a>] and reviewed by [<a href="">5</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Galanin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:37+01:00 Andrew L. Gundlach Philip J. Ryan Galanin receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">56</a>]</b>) are activated by the endogenous peptides <a href= "">galanin</a> and <a href= "">galanin-like peptide</a>. Human <a href= "">galanin</a> is a 30 amino-acid non-amidated peptide [<a href="">51</a>]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1&#8211;14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (<i>e.g</i>. human galanin-1&#8211;19 [<a href="">21</a>] and porcine galanin-5&#8211;29 [<a href="">166</a>]) and N-terminally extended forms (<i>e.g.</i> N-terminally seven and nine residue elongated forms of porcine galanin [<a href="">22</a>, <a href="">166</a>]) have been reported. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Ghrelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:41+01:00 Anthony P. Davenport Birgitte Holst Matthias Kleinz Janet J. Maguire Bjørn B. Sivertsen The ghrelin receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee for the Ghrelin receptor [<a href="">18</a>]</b>) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (<a href="!/hgnc_id/HGNC:18129"><i>GHRL</i></a>, <a href="">Q9UBU3</a>). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [<a href="">70</a>]. Alternative splicing results in the formation of a second peptide, <a href= "">[des-Gln<sup>14</sup>]ghrelin</a> with equipotent biological activity [<a href="">48</a>]. A unique post-translational modification (octanoylation of Ser<sup>3</sup>, catalysed by ghrelin &#927;-acyltransferase (<a href="!/hgnc_id/HGNC:32311"><i>MBOAT4</i></a>, <a href="">Q96T53</a>) [<a href="">127</a>] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [<a href="">56</a>]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [<a href="">4</a>], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of <a href= "">ghrelin</a> function [<a href="">43</a>]. In cell systems, the ghrelin receptor is constitutively active [<a href="">44</a>], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [<a href="">88</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Glucagon receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:44+01:00 Dominique Bataille Susan L. Chan Philippe Delagrange Daniel J. Drucker Burkhard Göke Rebecca Hills Kelly E. Mayo Laurence J. Miller Roberto Salvatori Bernard Thorens The glucagon family of receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the Glucagon receptor family [<a href="">159</a>]</b>) are activated by the endogenous peptide (27-44 aa) hormones <a href= "">glucagon</a>, <a href= "">glucagon-like peptide 1</a>, <a href= "">glucagon-like peptide 2</a>, glucose-dependent insulinotropic polypeptide (also known as <a href= "">gastric inhibitory polypeptide</a>), <a href= "">GHRH</a> and <a href= "">secretin</a>. One common precursor (<a href="!/hgnc_id/HGNC:4191"><i>GCG</i></a>) generates <a href= "">glucagon</a>, <a href= "">glucagon-like peptide 1</a> and <a href= "">glucagon-like peptide 2</a> peptides [<a href="">116</a>]. For a recent review on review the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the signaling events associated with it, see de Graaf et al., 2016 [<a href="">87</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Glycoprotein hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:47+01:00 Sabine Costagliola James A. Dias Marvin Gershengorn Deborah L. Segaloff Axel P.N. Themmen Gilbert Vassart Glycoprotein hormone receptors (<b>provisional nomenclature [<a href="">45</a>]</b>) are activated by a non-covalent heterodimeric glycoprotein made up of a common &#945; chain (<a href= "">glycoprotein hormone common alpha subunit</a> <a href="!/hgnc_id/HGNC:1885"><i>CGA</i></a>, <a href="">P01215</a>), with a unique &#946; chain that confers the biological specificity to <a href= "">FSH</a>, <a href= "">LH</a>, <a href= "">hCG</a> or <a href= "">TSH</a>. There is binding cross-reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors [<a href="">120</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Gonadotrophin-releasing hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:50+01:00 Laura H. Heitman Adriaan P. IJzerman Craig A. McArdle Adam J. Pawson GnRH<sub>1</sub> and GnRH<sub>2</sub> receptors (<b>provisonal nomenclature [<a href="">35</a>]</b>, also called Type I and Type II GnRH receptor, respectively [<a href="">78</a>]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [<a href="">78</a>, <a href="">77</a>, <a href="">107</a>]. <a href= "">GnRH I</a> (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [<a href="">78</a>, <a href="">77</a>, <a href="">107</a>] including <a href= "">GnRH II</a> (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH<sub>2</sub> (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [<a href="">78</a>, <a href="">77</a>, <a href="">107</a>]. GnRH<sub>1</sub> receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [<a href="">53</a>]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [<a href="">53</a>]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH<sub>2</sub> receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [<a href="">81</a>]. Phylogenetic classifications divide GnRH receptors into three [<a href="">78</a>] or five groups [<a href="">122</a>] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Histamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:51+01:00 Paul Chazot Marlon Cowart Hiroyuki Fukui C. Robin Ganellin Ralf Gutzmer Helmut L. Haas Stephen J. Hill Rebecca Hills Rob Leurs Roberto Levi Steve Liu Pertti Panula Walter Schunack Jean-Charles Schwartz Roland Seifert Nigel P. Shankley Holger Stark Robin Thurmond Henk Timmerman J. Michael Young Histamine receptors (<b>nomenclature as agreed by the <u> NC-IUPHAR</u> Subcommittee on Histamine Receptors [<a href="">75</a>, <a href="">163</a>]</b>) are activated by the endogenous ligand <a href= "">histamine</a>. Marked species differences exist between histamine receptor orthologues [<a href="">75</a>]. The human and rat H<sub>3</sub> receptor genes are subject to significant splice variance [<a href="">12</a>]. The potency order of histamine at histamine receptor subtypes is H<sub>3</sub> = H<sub>4</sub> > H<sub>2</sub> > H<sub>1</sub> [<a href="">163</a>]. Some agonists at the human H<sub>3</sub> receptor display significant ligand bias [<a href="">171</a>]. Antagonists of all 4 histamine receptors have clinical uses: H<sub>1</sub> antagonists for allergies (<i>e.g. </i><a href= "">cetirizine</a>), H<sub>2</sub> antagonists for acid-reflux diseases (<i>e.g. </i><a href= "">ranitidine</a>), H<sub>3</sub> antagonists for narcolepsy (<i>e.g. </i><a href= "">pitolisant</a>/WAKIX; Registered) and H<sub>4</sub> antagonists for atopic dermatitis (<i>e.g. </i><a href= "">ZPL-3893787</a>; Phase IIa) [<a href="">163</a>] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [<a href="">205</a>, <a href="">8</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Kisspeptin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:54+01:00 Anthony P. Davenport Janet J. Maguire Edward J. Mead The kisspeptin receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the kisspeptin receptor [<a href="">9</a>]</b>), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. <a href= "">kisspeptin-54</a> (KP54, originally named metastin), <a href= "">kisspeptin-13</a> (KP13) and <a href= "">kisspeptin-10</a> (KP10) are biologically-active peptides cleaved from the <a href="!/hgnc_id/HGNC:6341"><i>KISS1</i></a> (<a href="">Q15726</a>) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Leukotriene receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:38:55+01:00 Magnus Bäck Charles Brink Nan Chiang NCHIANG@PARTNERS.ORG Sven-Erik Dahlén Gordon Dent Jeffrey Drazen Jilly F. Evans Douglas W. P. Hay Motonao Nakamura William Powell Joshua Rokach G. Enrico Rovati Charles N. Serhan Takao Shimizu Takehiko Yokomizo The leukotriene receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Leukotriene Receptors [<a href="">31</a>, <a href="">34</a>]</b>) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT<sub>1</sub> receptor is the high affinity LTB<sub>4</sub> receptor whereas the BLT<sub>2</sub> receptor in addition to being a low-affinity LTB<sub>4</sub> receptor also binds several other lipoxygenase-products, such as <a href= "">12S-HETE</a>, <a href= "">12S-HPETE</a>, <a href= "">15S-HETE</a>, and the thromboxane synthase product <a href= "">12-hydroxyheptadecatrienoic acid</a>. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB<sub>4</sub> has been reported to bind to the peroxisome proliferator activated receptor (PPAR) &#945; [<a href="">189</a>] and the vanilloid TRPV1 ligand-gated nonselective cation channel [<a href="">210</a>]. The receptors for the cysteinyl-leukotrienes (<i>i.e.</i> <a href= "">LTC<sub>4</sub></a>, <a href= "">LTD<sub>4</sub></a> and <a href= "">LTE<sub>4</sub></a>) are termed CysLT<sub>1</sub> and CysLT<sub>2</sub> and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT<sub>1</sub> and CysLT<sub>2</sub> receptors [<a href="">34</a>]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y<sub>12</sub> receptor [<a href="">91</a>, <a href="">236</a>, <a href="">265</a>], GPR17 [<a href="">53</a>] and GPR99 [<a href="">161</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Lysophospholipid (LPA) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:39:00+01:00 Victoria Blaho Jerold Chun Aaron Frantz Timothy Hla Danielle Jones Deepa Jonnalagadda Yasuyuki Kihara Hirotaka Mizuno Wouter Moolenaar Chido Mpamhanga Sarah Spiegel Valerie Tan Yun C. Yung Lysophosphatidic acid (LPA) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Lysophospholipid Receptors [<a href="">50</a>, <a href="">18</a>]</b>) are activated by the endogenous phospholipid <a href= "">LPA</a>. The first receptor, LPA<sub>1</sub>, was identified as <i>ventricular zone gene-1</i> (<i>vzg-1</i>) [<a href="">38</a>], leading to deorphanisation of members of the endothelial differentiation gene (<i>edg</i>) family as other LPA receptors along with sphingosine 1-phosphate (S1P) receptors. Additional LPA receptor GPCRs were later identified. Gene names have been codified as <i>LPAR1</i>, <i>etc</i>. to reflect the receptor function of proteins. The crystal structure of LPA<sub>1</sub> was solved and demonstrates extracellular LPA access to the binding pocket, consistent with proposed delivery <i>via</i> autotaxin [<a href="">12</a>]. These studies have also implicated cross-talk with endocannabinoids <i>via</i> phosphorylated intermediates that can also activate these receptors. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Binding affinities of unlabeled, natural LPA and AEAp to LPA<sub>1</sub> were measured using backscattering interferometry (pK<sub>d</sub> = 9) [<a href="">73</a>]. Binding affinities were 77-fold lower than than values obtained using radioactivity [<a href="">111</a>]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out <i>via</i> a novel TGF&#945; "shedding" assay [<a href="">45</a>]. <a href= "">LPA</a> has also been described as an agonist for the transient receptor potential (Trp) ion channel TRPV1 [<a href="">76</a>] and TRPA1 [<a href="">53</a>]. LPA was originally proposed to be a ligand for GPCR35, but data show that in fact it is a receptor for <a href= "">CXCL17</a> [<a href="">68</a>]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as <i>bona fide</i> LPA receptors. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Melanin-concentrating hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:39:02+01:00 Valérie Audinot Jean A. Boutin Bernard Lakaye Jean-Louis Nahon Yumito Saito Melanin-concentrating hormone (MCH) receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">31</a>]</b>) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor (<a href="!/hgnc_id/HGNC:9109"><i>PMCH</i></a>, <a href="">P20382</a>), which also produces <a href= "">neuropeptide EI</a> and <a href= "">neuropeptide GE</a>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Melanocortin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:39:04+01:00 Vanni Caruso Biao-Xin Chai Adrian J. L. Clark Roger D. Cone Alex N. Eberle Sadaf Farooqi Tung M. Fong Ira Gantz Carrie Haskell-Luevano Victor J. Hruby Kathleen G. Mountjoy Colin Pouton Helgi Schiöth Jeffrey B. Tatro Jarl E. S. Wikberg Melanocortin receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">36</a>]</b>) are activated by members of the melanocortin family (<a href= "">&#945;-MSH</a>, <a href= "">&#946;-MSH</a> and <a href= "">&#947;-MSH</a> forms; &#948; form is not found in mammals) and adrenocorticotrophin (<a href= "">ACTH</a>). Endogenous antagonists include <a href= "">agouti</a> and <a href= "">agouti-related protein</a>. ACTH(1-24) was approved by the US FDA as a diagnostic agent for adrenal function test, whilst NDP-MSH was approved by EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Melatonin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T15:39:06+01:00 Daniel P. Cardinali Philippe Delagrange Margarita L. Dubocovich Ralf Jockers Diana N. Krause Regina Pekelmann Markus James Olcese Jesús Pintor Nicolas Renault David Sugden Gianluca Tosini Darius Paul Zlotos Melatonin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR </u>Subcommittee on Melatonin Receptors [<a href="">36</a>]</b>) are activated by the endogenous ligands <a href= "">melatonin</a> and clinically used drugs like <a href= "">ramelteon</a>, <a href= "">agomelatine</a> and <a href= "">tasimelteon</a>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Metabotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:47+01:00 Francine Acher Giuseppe Battaglia Hans Bräuner-Osborne P. Jeffrey Conn Robert Duvoisin Francesco Ferraguti Peter J. Flor Cyril Goudet Karen J. Gregory David Hampson Michael P. Johnson Yoshihiro Kubo James Monn Shigetada Nakanishi Ferdinando Nicoletti Colleen Niswender Jean-Philippe Pin Philippe Rondard Darryle D. Schoepp Ryuichi Shigemoto Michihiro Tateyama Metabotropic glutamate (mGlu) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Metabotropic Glutamate Receptors [334]</b>) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate. The mGlu family is composed of eight members (named mGlu1 to mGlu8) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu<sub>1</sub> and mGlu<sub>5</sub>), Group-II (mGlu<sub>2</sub> and mGlu<sub>3</sub>) and Group-III (mGlu<sub>4</sub>, mGlu<sub>6</sub>, mGlu<sub>7</sub> and mGlu<sub>8</sub>) (see Further reading).<br><br>Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. The structures of the VFTD of mGlu<sub>1</sub>, mGlu<sub>2</sub>, mGlu<sub>3</sub>, mGlu<sub>5</sub> and mGlu<sub>7</sub> have been solved [<a href="">190</a>, <a href="">262</a>, <a href="">255</a>, <a href="">386</a>]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organization similar to that of other GPCRs, although the helices appear more compacted [<a href="">85</a>, <a href="">415</a>, <a href="">59</a>]. mGlu form constitutive dimers crosslinked by a disulfide bridge. Recent studies revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [<a href="">86</a>]. Although well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [<a href="">422</a>, <a href="">257</a>].<br><br> The endogenous ligands of mGlu are <a href= "">L-glutamic acid</a>, <a href= "">L-serine-O-phosphate</a>, N-acetylaspartylglutamate (<a href= "">NAAG</a>) and <a href= "">L-cysteine sulphinic acid</a>. Group-I mGlu receptors may be activated by <a href= "">3,5-DHPG</a> and <a href= "">(<i>S</i>)-3HPG</a> [<a href="">29</a>] and antagonized by <a href= "">(S)-hexylhomoibotenic acid</a> [<a href="">223</a>]. Group-II mGlu receptors may be activated by <a href= "">LY389795</a> [<a href="">256</a>], <a href= "">LY379268</a> [<a href="">256</a>], <a href= "">eglumegad</a> [<a href="">337</a>, <a href="">416</a>], <a href= "">DCG-IV</a> and <a href= "">(2<i>R</i>,3<i>R</i>)-APDC</a> [<a href="">338</a>], and antagonised by <a href= "">eGlu</a> [<a href="">161</a>] and <a href= "">LY307452</a> [<a href="">408</a>, <a href="">100</a>]. Group-III mGlu receptors may be activated by <a href= "">L-AP4</a> and <a href= "">(<i>R,S</i>)-4-PPG</a> [<a href="">125</a>]. An example of an antagonist selective for mGlu receptors is <a href= "">LY341495</a>, which blocks mGlu<sub>2</sub> and mGlu<sub>3</sub> at low nanomolar concentrations, mGlu<sub>8</sub> at high nanomolar concentrations, and mGlu<sub>4</sub>, mGlu<sub>5</sub>, and mGlu<sub>7</sub> in the micromolar range [<a href="">176</a>]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that bind within the TM domain have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as &#8216;potentiators&#8217; of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Motilin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:47+01:00 Anthony P. Davenport Motilin receptors (<b>provisional nomenclature</b>) are activated by <a href= "">motilin</a>, a 22 amino-acid peptide derived from a precursor (<a href="!/hgnc_id/HGNC:7141"><i>MLN</i></a>, <a href="">P12872</a>), which may also generate a <a href= "">motilin-associated peptide</a>. These receptors promote gastrointestinal motility and are suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; <i>e.g.</i> erythromycin), although for many of these molecules the evidence is sparse. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neuromedin U receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:47+01:00 Khaled Al-hosaini; Stephen R. Bloom Joseph Hedrick Andrew Howard Preeti Jethwa Simon Luckman Rita Raddatz Nina Semjonous Gary B. Willars Neuromedin U receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">29</a>]</b>) are activated by the endogenous 25 amino acid peptide neuromedin U (<a href= "">neuromedin U-25</a>, NmU-25), a peptide originally isolated from pig spinal cord [<a href="">90</a>]. In humans, NmU-25 appears to be the sole product of a precursor gene (<a href="!/hgnc_id/HGNC:7859"><i>NMU</i></a>, <a href="">P48645</a>) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (<a href= "">neuromedin S-33</a>) has also been identified as an endogenous agonist [<a href="">95</a>]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neuropeptide FF/neuropeptide AF receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:47+01:00 Catherine Mollereau-Manaute Lionel Moulédous Michel Roumy Kazuyoshi Tsutsui Takayoshi Ubuka Jean-Marie Zajac The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (<b>provisional nomenclature [<a href="">10</a>]</b>), which exhibit high affinities for neuropeptide FF (<a href="!/hgnc_id/HGNC:7901"><i>NPFF</i></a>, <a href="">O15130</a>) and RFamide related peptides (RFRP: precursor gene symbol <a href="!/hgnc_id/HGNC:13782">NPVF</a>, <a href="">Q9HCQ7</a>). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neuropeptide S receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:47+01:00 Girolamo Caló Olivier Civelli Rainer K. Reinscheid Chiara Ruzza The neuropeptide S receptor (NPS, <b>provisional nomenclature [<a href="">18</a>]</b>) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (<a href="!/hgnc_id/HGNC:33940"><i>NPS</i></a>, <a href="">P0C0P6</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neuropeptide W/neuropeptide B receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Anthony P. Davenport Janet J. Maguire Gurminder Singh The neuropeptide BW receptor 1 (NPBW1, <b>provisional nomenclature [<a href="">5</a>]</b>) is activated by two 23-amino-acid peptides, neuropeptide W (<a href= "">neuropeptide W-23</a>) and neuropeptide B (<a href= "">neuropeptide B-23</a>) [<a href="">20</a>, <a href="">6</a>]. C-terminally extended forms of the peptides (<a href= "">neuropeptide W-30</a> and <a href= "">neuropeptide B-29</a>) also activate NPBW1 [<a href="">2</a>]. Unique to both forms of neuropeptide B is the N-terminal bromination of the first tryptophan residue, and it is from this post-translational modification that the nomenclature NPB is derived. These peptides were first identified from bovine hypothalamus and therefore are classed as neuropeptides. Endogenous variants of the peptides without the N-terminal bromination, <a href= "">des-Br-neuropeptide B-23</a> and <a href= "">des-Br-neuropeptide B-29</a>, were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C-terminal extended forms of neuropeptide W and neuropeptide B [<a href="">2</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neuropeptide Y receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Annette Beck-Sickinger William F. Colmers Helen M. Cox Henri N. Doods Herbert Herzog Dan Larhammar Martin C. Michel Remi Quirion Thue Schwartz Thomas Westfall Neuropeptide Y (NPY) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Neuropeptide Y Receptors [<a href="">156</a>]</b>) are activated by the endogenous peptides <a href= "">neuropeptide Y</a>, neuropeptide Y-(3-36), <a href= "">peptide YY</a>, PYY-(3-36) and <a href= "">pancreatic polypeptide</a> (PP). The receptor originally identified as the Y3 receptor has been identified as the <a href="ObjectDisplayForward?objectId=71">CXCR4 chemokine recepter</a> (originally named LESTR, [<a href="">137</a>]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene [<a href="">83</a>]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y<sub>4 </sub>receptor than at the human receptor [<a href="">61</a>]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [<sup>125</sup>I]-PYY or [<sup>125</sup>I]-NPY can be used to label Y<sub>1</sub>, Y<sub>2</sub>, Y<sub>5</sub> and y<sub>6</sub> subtypes non-selectively, while <a href= "">[<sup>125</sup>I][cPP(1-7), NPY(19-23), Ala<sup>31</sup>, Aib<sup>32</sup>, Gln<sup>34</sup>]hPP</a> may be used to label Y<sub>5</sub> receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Neurotensin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Jean Mazella Philippe Sarret Jean-Pierre Vincent Neurotensin receptors (<b>nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">38</a>]</b>) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (<a href="!/hgnc_id/HGNC:8038"><i>NTS</i></a>, <a href="">30990</a>), which also generates neuromedin N, an agonist at the NTS<sub>2</sub> receptor. <a href= "">[<sup>3</sup>H]neurotensin (human, mouse, rat)</a> and <a href= "">[<sup>125</sup>I]neurotensin (human, mouse, rat)</a> may be used to label NTS<sub>1</sub> and NTS<sub>2</sub> receptors at 0.1-0.3 and 3-5 nM concentrations respectively. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Hydroxycarboxylic acid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Steven L. Colletti Adriaan P. IJzerman Timothy W. Lovenberg Stefan Offermanns Graeme Semple M. Gerard Waters Alan Wise The hydroxycarboxylic acid family of receptors (<a href="">ENSFM00500000271913</a>, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Hydroxycarboxylic acid receptors [<a href="">32</a>, <a href="">10</a>]</b>) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and <a href= "">L-lactic acid</a>, as well as the lipid lowering agents <a href= "">nicotinic acid</a> (niacin), <a href= "">acipimox</a> and <a href= "">acifran</a> [<a href="">47</a>, <a href="">54</a>, <a href="">57</a>]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA<sub>2 </sub>receptors only and is unlikely to be the natural ligand [<a href="">54</a>, <a href="">57</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Opioid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Anna Borsodi Michael Bruchas Girolamo Caló Charles Chavkin MacDonald J. Christie Olivier Civelli Mark Connor Brian M. Cox Lakshmi A. Devi Christopher Evans Volker Höllt Graeme Henderson Stephen Husbands Eamonn Kelly Brigitte Kieffer Ian Kitchen Mary-Jeanne Kreek Lee-Yuan Liu-Chen Dominique Massot Jean-Claude Meunier Philip S. Portoghese Stefan Schulz Toni S. Shippenberg Eric J. Simon Lawrence Toll John R. Traynor Hiroshi Ueda Yung H. Wong Nurulain Zaveri Andreas Zimmer Opioid and opioid-like receptors are activated by a variety of endogenous peptides including <a href= "">[Met]enkephalin</a> (met), <a href= "">[Leu]enkephalin</a> (leu), <a href= "">&#946;-endorphin</a> (&#946;-end), <a href= "">&#945;-neodynorphin</a>, <a href= "">dynorphin A</a> (dynA), <a href= "">dynorphin B</a> (dynB), <a href= "">big dynorphin</a> (Big dyn), <a href= "">nociceptin/orphanin FQ</a> (N/OFQ); <a href= "">endomorphin-1</a> and <a href= "">endomorphin-2</a> are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, &#956;, &#948; and &#954;, is well established, and <u><b>NC-IUPHAR</b></u> considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP. [<a href="">116</a>, <a href="">96</a>, <a href="">88</a>]. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [<a href="">282</a>], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as <a href= "">morphine</a> and many other opioid analgesics, as well as antagonists such as <a href= "">naloxone</a>, however only for the &#956; receptor. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Orexin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Paul Coleman Luis de Lecea Anthony Gotter Jim Hagan Rebecca Hills Thomas Kilduff Jyrki P. Kukkonen Rod Porter John Renger Jerome M Siegel Gregor Sutcliffe Neil Upton Christopher J. Winrow Orexin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Orexin receptors [<a href="">39</a>]</b>) are activated by the endogenous polypeptides <a href= "">orexin-A</a> and <a href= "">orexin-B</a> (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, <a href="!/hgnc_id/HGNC:4847">preproorexin or orexin precursor</a>, by proteolytic cleavage and some typical peptide modifications [<a href="">102</a>]. Currently the only orexin receptor ligand in clinical use is <a href= "">suvorexant</a>, which is used as a hypnotic. Orexin receptor crystal structures have been solved [<a href="">124</a>, <a href="">123</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## P2Y receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Maria-Pia Abbracchio Jean-Marie Boeynaems José L. Boyer Geoffrey Burnstock Stefania Ceruti Marta Fumagalli Christian Gachet Rebecca Hills Robert G. Humphries Kazu Inoue Kenneth A. Jacobson Charles Kennedy Brian F. King Davide Lecca Christa E. Müller Maria Teresa Miras-Portugal Vera Ralevic Gary A. Weisman P2Y receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on P2Y Receptors [<a href="">3</a>, <a href="">5</a>]</b>) are activated by the endogenous ligands <a href= "">ATP</a>, <a href= "">ADP</a>, <a href= "">uridine triphosphate</a>, <a href= "">uridine diphosphate</a> and <a href= "">UDP-glucose</a>. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as '<a href= "">uridine triphosphate</a>-preferring (or <a href= "">ATP</a>-, <i>etc</i>.) P2Y receptor' or 'P2Y<sub>1</sub>-like', <i>etc.</i>, until further, as yet undefined, corroborative criteria can be applied [46, <a href="">109</a>, <a href="">187</a>, <a href="">375</a>, <a href="">388</a>].<br><br>Clinically used drugs acting on these receptors include the dinucleoside polyphosphate <a href= "">diquafosol</a>, agonist of the P2Y<sub>2</sub> receptor subtype, approved in Japan for the management of dry eye disease [<a href="">236</a>], and the P2Y<sub>12</sub> receptor antagonists <a href= "">prasugrel</a>, <a href= "">ticagrelor</a> and <a href= "">cangrelor</a>, all approved as antiplatelet drugs [<a href="">52</a>, <a href="">316</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Parathyroid hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Alessandro Bisello Michael Chorev Peter A. Friedman Tom Gardella Rebecca Hills Harald Jueppner T. John Martin Robert A. Nissenson John Thomas Potts, Jr. JTPOTTS@PARTNERS.ORG Caroline Silve Ted B. Usdin Jean-Pierre Vilardaga The parathyroid hormone receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Parathyroid Hormone Receptors [<a href="">47</a>]</b>) are family B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1 receptor) is activated by precursor-derived peptides: <a href= "">PTH</a> (84 amino acids), and <a href= "">PTHrP</a> (141 amino-acids) and related peptides (PTH-(1-34), <a href= "">PTHrP-(1-36)</a>). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide <a href= "">TIP39</a> (39 amino acids). [<sup>125</sup>I]PTH may be used to label both PTH1 and PTH2 receptors. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## QRFP receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:46+01:00 Didier Bagnol Tom I. Bonner Myrna Carlebur Anthony P. Davenport Stephen M. Foord Shoji Fukusumi Riccarda Granata Dan Larhammar Jérôme Leprince Janet J. Maguire Stefany D. Primeaux Hubert Vaudry The human gene encoding the QRFP receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the QRFP receptor [<a href="">16</a>]</b>; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee <i>et al.</i> from a hypothalamus cDNA library [<a href="">15</a>]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y<sub>2</sub> (37%) and galanin Gal<sub>1</sub> (35%) receptors. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Platelet-activating factor receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Rebecca Hills Satoshi Ishii Sonia Jancar Thomas McIntyre Ewa Ninio Chris O'Neill Francisco Jose Oliveira Rios Jeffery B. Travers Mark Whittaker Platelet-activating factor (<a href= "">PAF</a>, 1-<em>O</em>-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (<b>provisional nomenclature recommended by <u>NC-IUPHAR</u> [<a href="">37</a>]</b>) is activated by <a href= "">PAF</a> and other suggested endogenous ligands are oxidized phosphatidylcholine [<a href="">73</a>] and <a href= "">lysophosphatidylcholine</a> [<a href="">96</a>]. It may also be activated by bacterial lipopolysaccharide [<a href="">89</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Prokineticin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Rebecca Hills Philippe Rondard Oualid Sbai Qun-Yong Zhou Prokineticin receptors, PKR<sub>1</sub> and PKR<sub>2</sub> (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">23</a>]</b>) respond to the cysteine-rich 81-86 amino-acid peptides <a href= "">prokineticin-1</a> (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and <a href= "">prokineticin-2</a> (protein Bv8 homologue). An orthologue of PROK1 from black mamba (<em>Dendroaspis polylepi</em>s) venom, mamba intestinal toxin 1 (<a href= "">MIT1</a>, [<a href="">65</a>]) is a potent, non-selective agonist at prokineticin receptors [<a href="">41</a>], while <a href= "">Bv8</a>, an orthologue of PROK2 from amphibians (<em>Bombina sp.</em>, [<a href="">44</a>]), is equipotent at recombinant PKR<sub>1</sub> and PKR<sub>2</sub> [<a href="">48</a>], and has high potency in macrophage chemotaxis assays, which are lost in PKR<sub>1</sub>-null mice. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Prolactin-releasing peptide receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Vanni Caruso Rebecca Hills Malin Lagerstrom Tatsushi Onaka Helgi Schiöth The precursor (<a href="!/hgnc_id/HGNC:17945"><i>PRLH</i></a>, <a href="">P81277</a>) for PrRP generates 31 and 20-amino-acid versions. <a href= "">QRFP43</a> (named after a pyroglutamylated arginine-phenylalanine-amide peptide) is a 43 amino acid peptide derived from <a href="!/hgnc_id/HGNC:29982">QRFP</a> (<a href="">P83859</a>) and is also known as P518 or 26RFa. RFRP is an RF amide-related peptide [<a href="">29</a>] derived from a FMRFamide-related peptide precursor (<a href="!/hgnc_id/HGNC:13782"><i>NPVF</i></a>, <a href="">Q9HCQ7</a>), which is cleaved to generate <a href= "">neuropeptide SF</a>, neuropeptide <a href= "">RFRP-1</a>, neuropeptide <a href= "">RFRP-2</a> and neuropeptide <a href= "">RFRP-3</a> (neuropeptide NPVF). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Prostanoid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Richard M. Breyer Lucie Clapp Robert A. Coleman Mark Giembycz Akos Heinemann Rebecca Hills Robert L. Jones Shuh Narumiya Xavier Norel Roy Pettipher Yukihiko Sugimoto David F. Woodward Chengcan Yao Prostanoid receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Prostanoid Receptors [<a href="">644</a>]</b>) are activated by the endogenous ligands prostaglandins <a href= "">PGD<sub>2</sub></a>, <a href= "">PGE<sub>1</sub></a>, <a href= "">PGE<sub>2</sub></a> , <a href= "">PGF<sub>2&#945;</sub></a>, <a href= "">PGH<sub>2</sub></a>, prostacyclin [<a href= "">PGI<sub>2</sub></a>] and <a href= "">thromboxane A<sub>2</sub></a>. Measurement of the potency of <a href= "">PGI<sub>2</sub></a> and <a href= "">thromboxane A<sub>2</sub></a> is hampered by their instability in physiological salt solution; they are often replaced by <a href= "">cicaprost</a> and <a href= "">U46619</a>, respectively, in receptor characterization studies. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Proteinase-activated receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Nigel Bunnett Kathryn DeFea Justin Hamilton Morley D. Hollenberg Rithwik Ramachandran JoAnn Trejo Proteinase-activated receptors (PARs, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Proteinase-activated Receptors [<a href="">35</a>]</b>) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are <a href= "">SFLLRN-NH<sub>2</sub></a>, <a href= "">SLIGKV-NH<sub>2</sub></a>, <a href= "">TFRGAP-NH<sub>2</sub></a> and <a href= "">GYPGQV-NH<sub>2</sub></a>, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of G&#945;q-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [<a href="">73</a>]. PAR2 ectivation by NE regulates inflammation and pain responses [<a href="">101</a>, <a href="">65</a>] and triggers mucin secretion from airway epithelial cells [<a href="">102</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Relaxin family peptide receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Ross Bathgate Thomas Dschietzig Andrew L. Gundlach Michelle Halls Roger Summers Relaxin family peptide receptors (RXFP, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Relaxin family peptide receptors [<a href="">18</a>, <a href="">75</a>]</b>) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: <a href= "">relaxin-1</a>, <a href= "">relaxin</a>, <a href= "">relaxin-3</a> (also known as INSL7), insulin-like peptide 3 (<a href= "">INSL3</a>) and <a href= "">INSL5</a>. Species homologues of relaxin have distinct pharmacology and <a href= "">relaxin</a> interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [<a href="">172</a>]. <a href= "">relaxin-3</a> is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [<a href="">170</a>]. <a href= "">INSL5</a> is the ligand for RXFP4 but is a weak antagonist of RXFP3. <a href= "">relaxin</a> and <a href= "">INSL3</a> have multiple complex binding interactions with RXFP1 [<a href="">176</a>] and RXFP2 [<a href="">84</a>] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [<a href="">173</a>]. <a href= "">INSL5</a> and <a href= "">relaxin-3</a> interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [<a href="">211</a>, <a href="">97</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Somatostatin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Corinne Bosquet Justo P. Castaño Zsolt Csaba Micheal Culler Pascal Dournaud Jacques Epelbaum Wasyl Feniuk Anthony Harmar Rebecca Hills Leo Hofland Daniel Hoyer Patrick P. A. Humphrey Hans-Jürgen Kreienkamp Amelie Lupp Shlomo Melmed Wolfgang Meyerhof Anne-Marie O'Carroll Yogesh C. Patel Terry Reisine Jean-Claude Reubi Marcus Schindler Herbert Schmid Agnes Schonbrunn Stefan Schulz John E. Taylor Giovanni Tulipano Annamaria Vezzani Hans-Jürgen Wester Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST<sub>1</sub>-SST<sub>5</sub>; <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Somatostatin Receptors [<a href="">89</a>]</b>). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 (<a href= "">SRIF-14</a>) and somatostatin-28 (<a href= "">SRIF-28</a>). <a href= "">cortistatin-14</a> has also been suggested to be an endogenous ligand for somatostatin receptors [<a href="">56</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Tachykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Jeffrey Barrett Brenden Canning Joseph Coulson Erin Dombrowsky Steven D. Douglas Tung M. Fong Christa Y. Heyward Susan E. Leeman Pranela Remeshwar Tachykinin receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">90</a>]</b>) are activated by the endogenous peptides <a href= "">substance P</a> (SP), <a href= "">neurokinin A</a> (NKA; previously known as substance K, neurokinin &#945;, neuromedin L), <a href= "">neurokinin B</a> (NKB; previously known as neurokinin &#946;, neuromedin K), <a href= "">neuropeptide K</a> and <a href= "">neuropeptide &#947;</a> (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in <i>in vitro</i> pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as <a href= "">aprepitant</a> and <a href= "">fosaprepitant</a> were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Thyrotropin-releasing hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Anthony P. Davenport Marvin Gershengorn Rebecca Hills Thyrotropin-releasing hormone (TRH) receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">13</a>]</b>) are activated by the endogenous tripeptide <a href= "">TRH</a> (pGlu-His-ProNH2). <a href= "">TRH</a> and TRH analogues fail to distinguish TRH<sub>1</sub> and TRH<sub>2</sub> receptors [<a href="">28</a>]. <a href= "">[<sup>3</sup>H]TRH (human, mouse, rat)</a> is able to label both TRH<sub>1</sub> and TRH<sub>2</sub> receptors with K<sub>d</sub> values of 13 and 9 nM respectively. Synthesis and biology of ring-modified L-Histidine containing TRH analogues has been reported [<a href="">22</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Trace amine receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:45+01:00 Tom I. Bonner Anthony P. Davenport Stephen M. Foord Janet J. Maguire William A.E. Parker Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [<a href="">9</a>], where 15 mammalian orthologues were identified and divided into two families. The TA<sub>1</sub> receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee for the Trace amine receptor [<a href="">53</a>]</b>) has affinity for the endogenous trace amines <a href= "">tyramine</a>, <a href= "">&#946;-phenylethylamine</a> and <a href= "">octopamine</a> in addition to the classical amine <a href= "">dopamine</a> [<a href="">9</a>]. Emerging evidence suggests that TA<sub>1</sub> is a modulator of monoaminergic activity in the brain [<a href="">90</a>] with TA<sub>1</sub> and dopamine D<sub>2</sub> receptors shown to form constitutive heterodimers when co-expressed [<a href="">28</a>]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Urotensin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Anthony P. Davenport Stephen A. Douglas Alain Fournier Adel Giaid Henry Krum David G. Lambert Jérôme Leprince Margaret R. MacLean Eliot H. Ohlstein Walter G. Thomas Hervé Tostivint David Vaudry Hubert Vaudry David J. Webb The urotensin-II (U-II) receptor (UT, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the Urotensin receptor [26, <a href="">36</a>, <a href="">89</a>]</b>) is activated by the endogenous dodecapeptide <a href= "">urotensin-II</a>, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [<a href="">7</a>, <a href="">88</a>]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene <em>gpr14</em> [<a href="">20</a>, <a href="">62</a>, <a href="">68</a>, <a href="">70</a>]. Human <a href= "">urotensin-II</a>, an 11-amino-acid peptide [<a href="">20</a>], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [<a href="">53</a>, <a href="">11</a>]. This sequence is also conserved in the deduced amino-acid sequence of rat <a href= "">urotensin-II</a> (14 amino-acids) and mouse <a href= "">urotensin-II</a> (14 amino-acids), although the N-terminal is more divergent from the human sequence [<a href="">19</a>]. A second endogenous ligand for the UT has been discovered in rat [<a href="">83</a>]. This is the <a href= "">urotensin II-related peptide</a>, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat <a href= "">urotensin II-related peptide</a> are predicted for the mature mouse and human peptides [<a href="">32</a>]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [<a href="">89</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Vasopressin and oxytocin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Daniel Bichet Michel Bouvier Bice Chini Gerald Gimpl Gilles Guillon Tadashi Kimura Mark Knepper Stephen Lolait Maurice Manning Bernard Mouillac Anne-Marie O'Carroll Claudine Serradeil-Le Gal Melvyn Soloff Joseph G. Verbalis Mark Wheatley Hans H. Zingg Vasopressin (AVP) and oxytocin (OT) receptors (<b>nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">92</a>]</b>) are activated by the endogenous cyclic nonapeptides <a href= "">vasopressin</a> and <a href= "">oxytocin</a>. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [<a href="">67</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## VIP and PACAP receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Jan Fahrenkrug Edward J. Goetzl Illana Gozes Anthony Harmar Marc Laburthe Victor May Joseph R. Pisegna Sami I. Said David Vaudry Hubert Vaudry James A. Waschek Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Vasoactive Intestinal Peptide Receptors [<a href="">64</a>, <a href="">65</a>]</b>) are activated by the endogenous peptides <a href= "">VIP</a>, <a href= "">PACAP-38</a>, <a href= "">PACAP-27</a>, peptide histidine isoleucineamide (<a href= "">PHI</a>), peptide histidine methionineamide (<a href= "">PHM</a>) and peptide histidine valine (<a href= "">PHV</a>). VPAC<sub>1</sub> and VPAC<sub>2</sub> receptors display comparable affinity for the PACAP peptides, <a href= "">PACAP-27</a> and <a href= "">PACAP-38</a>, and <a href= "">VIP</a>, whereas <a href= "">PACAP-27</a> and <a href= "">PACAP-38</a> are >100 fold more potent than <a href= "">VIP</a> as agonists of most isoforms of the PAC<sub>1</sub> receptor. However, one splice variant of the human PAC<sub>1</sub> receptor has been reported to respond to <a href= "">PACAP-38</a>, <a href= "">PACAP-27</a> and <a href= "">VIP</a> with comparable affinity [<a href="">29</a>]. <a href= "">PG 99-465</a> [<a href="">115</a>] has been used as a selective VPAC<sub>2 </sub>receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC<sub>1</sub> and PAC<sub>1</sub> receptors [<a href="">35</a>]. The selective PAC<sub>1</sub> receptor agonist <a href= "">maxadilan</a>, was extracted from the salivary glands of sand flies (<i>Lutzomyia longipalpis</i>) and has no sequence homology to <a href= "">VIP</a> or the PACAP peptides [<a href="">116</a>]. Two deletion variants of <a href= "">maxadilan</a>, <a href= "">M65</a> [<a href="">180</a>] and <a href= "">Max.d.4</a> [<a href="">117</a>] have been reported to be PAC<sub>1</sub> receptor antagonists, but these peptides have not been extensively characterised. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 5-HT<sub>3</sub> receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Nicholas M. Barnes Tim G. Hales Sarah C. R. Lummis Beate Niesler John A. Peters The 5-HT<sub>3</sub> receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR </u>Subcommittee on 5-Hydroxytryptamine (serotonin) receptors [<a href="">66</a>]</b>) is a ligand-gated ion channel of the Cys-loop family that includes the zinc-activated channels, nicotinic acetylcholine, GABA<sub>A </sub>and strychnine-sensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel [<a href="">5</a>]. Five human 5-HT<sub>3</sub> receptor subunits have been cloned and homo-oligomeric assemblies of 5-HT<sub>3</sub>A and hetero-oligomeric assemblies of 5-HT<sub>3</sub>A and 5-HT<sub>3</sub>B subunits have been characterised in detail. The 5-HT<sub>3</sub>C (<a href="!/hgnc_id/HGNC:24003"><i>HTR3C</i></a>, <a href="">Q8WXA8</a>), 5-HT<sub>3</sub>D (<a href="!/hgnc_id/HGNC:24004"><i>HTR3D</i></a>, <a href="">Q70Z44</a>) and 5-HT<sub>3</sub>E (<a href="!/hgnc_id/HGNC:24005"><i>HTR3E</i></a>, <a href="">A5X5Y0</a>) subunits [<a href="">83</a>, <a href="">122</a>], like the 5-HT<sub>3</sub>B subunit, do not form functional homomers, but are reported to assemble with the 5-HT<sub>3</sub>A subunit to influence its functional expression rather than pharmacological profile [<a href="">124</a>, <a href="">63</a>, <a href="">157</a>]. 5-HT<sub>3</sub>A, -C, -D, and -E subunits also interact with the chaperone RIC-3 which predominantly enhances the surface expression of homomeric 5-HT<sub>3</sub>A receptor [<a href="">157</a>]. The co-expression of 5-HT<sub>3</sub>A and 5-HT<sub>3</sub>C-E subunits has been demonstrated in human colon [<a href="">82</a>]. A recombinant hetero-oligomeric 5-HT<sub>3</sub>AB receptor has been reported to contain two copies of the 5-HT<sub>3</sub>A subunit and three copies of the 5-HT<sub>3</sub>B subunit in the order B-B-A-B-A [<a href="">7</a>], but this is inconsistent with recent reports which show at least one A-A interface [<a href="">96</a>, <a href="">150</a>]. The 5-HT<sub>3</sub>B subunit imparts distinctive biophysical properties upon hetero-oligomeric 5-HT<sub>3</sub>AB versus homo-oligomeric 5-HT<sub>3</sub>A recombinant receptors [<a href="">32</a>, <a href="">41</a>, <a href="">56</a>, <a href="">85</a>, <a href="">139</a>, <a href="">129</a>, <a href="">79</a>], influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists ([<a href="">17</a>], but see [<a href="">41</a>, <a href="">30</a>, <a href="">35</a>]) which may be explained by the orthosteric binding site residing at an interface formed between 5-HT<sub>3</sub>A subunits [<a href="">96</a>, <a href="">150</a>]. However, 5-HT<sub>3</sub>A and 5-HT<sub>3</sub>AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles [<a href="">138</a>, <a href="">135</a>, <a href="">71</a>]. The potential diversity of 5-HT<sub>3</sub> receptors is increased by alternative splicing of the genes HTR3A and E [<a href="">64</a>, <a href="">19</a>, <a href="">124</a>, <a href="">123</a>, <a href="">120</a>]. In addition, the use of tissue-specific promoters driving expression from different transcriptional start sites has been reported for the<i> HTR3A,</i> <i>HTR3B,</i><i> HTR3D</i> and <i>HTR3E</i> genes, which could result in 5-HT<sub>3</sub> subunits harbouring different N-termini [<a href="">152</a>, <a href="">79</a>, <a href="">120</a>]. To date, inclusion of the 5-HT<sub>3</sub>A subunit appears imperative for 5-HT<sub>3</sub> receptor function. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Calcium- and sodium-activated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Richard Aldrich K. George Chandy Stephan Grissmer George A. Gutman GAGutman@UCI.Edu Leonard K. Kaczmarek Aguan D. Wei Heike Wulff Calcium- and sodium- activated potassium channels are members of the 6TM family of K channels which comprises the voltage-gated K<sub>V </sub>subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Ca<sup>2+</sup>-activated Slo subfamily (actually with 6 or 7TM) and the Ca<sup>2+</sup>- and Na<sup>+</sup>-activated SK subfamily (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Calcium- and sodium-activated potassium channels</b> [<a href="">124</a>]). As for the 2TM family, the pore-forming a subunits form tetramers and heteromeric channels may be formed within subfamilies (<i>e.g.</i> K<sub>V</sub>1.1 with K<sub>V</sub>1.2; KCNQ2 with KCNQ3). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## CatSper and Two-Pore channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Jean-Ju Chung David E. Clapham David L. Garbers Dejian Ren CatSper channels (CatSper1-4, <b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">13</a>]</b>) are putative 6TM, voltage-gated, alkalinization-activated calcium permeant channels that are presumed to assemble as a tetramer of &#945;-like subunits and mediate the current I<sub>CatSper</sub> [<a href="">21</a>]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltage-activated calcium channels (Ca<sub>v</sub>) [<a href="">36</a>]. CatSper1 [<a href="">36</a>], CatSper2 [<a href="">33</a>] and CatSpers 3 and 4 [<a href="">25</a>, <a href="">19</a>, <a href="">32</a>], in common with a putative 2TM auxiliary CatSper&#946; protein [<a href="">24</a>] and two putative 1TM associated CatSper&#947; and CatSper&#948; proteins [<a href="">42</a>, <a href="">11</a>], are restricted to the testis and localised to the principle piece of sperm tail. The novel cross-species CatSper channel inhibitor, <a href= "">RU1968</a>, has been proposed as a useful tool to aid characterisation of native CatSper channels [<a href="">37</a>].<br><br>Two-pore channels (TPCs) are structurally related to CatSpers, Ca<sub>V</sub>s and Na<sub>V</sub>s. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of Ca<sub>V</sub>s. There are three animal TPCs (TPC1-TPC3). Humans have TPC1 and TPC2, but not TPC3. TPC1 and TPC2 are localized in endosomes and lysosomes [<a href="">4</a>]. TPC3 is also found on the plasma membrane and forms a voltage-activated, non-inactivating Na<sup>+</sup> channel [<a href="">5</a>]. All the three TPCs are Na<sup>+</sup>-selective under whole-cell or whole-organelle patch clamp recording [<a href="">44</a>, <a href="">7</a>, <a href="">6</a>]. The channels may also conduct Ca<sup>2+</sup> [<a href="">29</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Cyclic nucleotide-regulated channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Elvir Becirovic Martin Biel Verena Hammelmann Franz Hofmann U. Benjamin Kaupp <b>Cyclic nucleotide-gated (CNG) channels</b> are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.<br><br>CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [<a href="">69</a>, <a href="">98</a>], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular <a href= "">cyclic GMP</a> level. This results in a closure of CNG channels and a reduced &#8216;dark current&#8217;. Similar channels were found in the cilia of olfactory neurons [<a href="">153</a>] and the pineal gland [<a href="">60</a>]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.<br><br><b>Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)</b><br>The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides <a href= "">cyclic AMP</a> and <a href= "">cyclic GMP</a> directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [<a href="">56</a>, <a href="">164</a>]. In native cells, these currents have a variety of names, such as <i>I</i><sub>h</sub>, <i>I</i><sub>q</sub> and<i> I</i><sub>f</sub>. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [<a href="">2</a>]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [<a href="">117</a>, <a href="">121</a>]. <b>A standardised nomenclature for CNG and HCN channels has been proposed by the <u>NC-IUPHAR</u> subcommittee on voltage-gated ion channels [<a href="">88</a>].</b> 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## GABA<sub>A</sub> receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Delia Belelli Tim G. Hales Jeremy J. Lambert Bernhard Luscher Richard Olsen John A. Peters Uwe Rudolph Werner Sieghart The GABA<sub>A</sub> receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT<sub>3</sub> and strychnine-sensitive glycine receptors. GABA<sub>A</sub> receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed &#8216;GABA<sub>A</sub>, slow&#8217; [<a href="">41</a>]. GABA<sub>A</sub> receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six &#945;, three &#946;, three &#947;, one &#948;, three &#961;, one &#949;, one &#960; and one &#952; GABA<sub>A</sub> receptor subunits have been reported in mammals [<a href="">273</a>, <a href="">232</a>, <a href="">231</a>, <a href="">278</a>]. The &#960;-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. &#945;4- and &#945;6- (both not functional) &#945;5-, &#946;2-, &#946;3- and &#947;2), along with RNA editing of the &#945;3 subunit [<a href="">67</a>]. The three &#961;-subunits, (&#961;1-3) function as either homo- or hetero-oligomeric assemblies [<a href="">354</a>, <a href="">46</a>]. Receptors formed from &#961;-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABA<sub>C</sub> receptors [<a href="">354</a>], <b>but they are classified as GABA<sub>A</sub> receptors by <u>NC-IUPHAR</u> on the basis of structural and functional criteria [<a href="">14</a>, <a href="">232</a>, <a href="">231</a>]</b>.<br><br>Many GABA<sub>A</sub> receptor subtypes contain &#945;-, &#946;- and &#947;-subunits with the likely stoichiometry 2&#945;.2&#946;.1&#947; [<a href="">164</a>, <a href="">232</a>]. It is thought that the majority of GABA<sub>A</sub> receptors harbour a single type of &#945;- and &#946; -subunit variant. The &#945;1&#946;2&#947;2 hetero-oligomer constitutes the largest population of GABA<sub>A</sub> receptors in the CNS, followed by the &#945;2&#946;3&#947;2 and &#945;3&#946;3&#947;2 isoforms. Receptors that incorporate the &#945;4- &#945;5-or &#945;6-subunit, or the &#946;1-, &#947;1-, &#947;3-, &#948;-, &#949;- and &#952;-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain &#945;6- and &#948;-subunits in cerebellar granule cells, or an &#945;4- and &#948;-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [<a href="">205</a>, <a href="">268</a>, <a href="">79</a>, <a href="">17</a>, <a href="">283</a>]. GABA binding occurs at the &#946;+/&#945;- subunit interface and the homologous &#947;+/&#945;- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the &#945;+/&#946;- interface ([<a href="">250</a>]; reviewed by [<a href="">277</a>]). The particular &#945;-and &#947;-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either &#945;4- or &#945;6-subunits are not recognised by &#8216;classical&#8217; benzodiazepines, such as <a href= "">flunitrazepam</a> (but see [<a href="">351</a>]). The trafficking, cell surface expression, internalisation and function of GABA<sub>A</sub> receptors and their subunits are discussed in detail in several recent reviews [<a href="">48</a>, <a href="">136</a>, <a href="">184</a>, <a href="">311</a>] but one point worthy of note is that receptors incorporating the &#947;2 subunit (except when associated with &#945;5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the d subunit appear to be exclusively extrasynaptic. <br><br><b><u>NC-IUPHAR</u> [<a href="">14</a>, <a href="">232</a>]</b> class the GABA<sub>A</sub> receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABA<sub>A</sub> receptors are classed as conclusively identified (<i>i.e</i>., &#945;1&#946;2&#947;2, &#945;1&#946;&#947;2, &#945;3&#946;&#947;2, &#945;4&#946;&#947;2, &#945;4&#946;2&#948;, &#945;4&#946;3&#948;, &#945;5&#946;&#947;2, &#945;6&#946;&#947;2, &#945;6&#946;2&#948;, &#945;6&#946;3&#948; and &#961;) with further receptor isoforms occurring with high probability, or only tentatively [<a href="">232</a>, <a href="">231</a>]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABA<sub>A</sub> receptor isoforms in detail; such information can be gleaned in the reviews [<a href="">14</a>, <a href="">91</a>, <a href="">164</a>, <a href="">169</a>, <a href="">140</a>, <a href="">273</a>, <a href="">212</a>, <a href="">232</a>, <a href="">231</a>] and [<a href="">8</a>, <a href="">7</a>]. Agents that discriminate between &#945;-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via &#946;-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of &#961; receptors is summarised in the table and additional aspects are reviewed in [<a href="">354</a>, <a href="">46</a>, <a href="">141</a>, <a href="">219</a>].<br/><br/>Several high-resolution cryo-electron microscopy structures have been described in which the full-length human &#945;1&#946;3&#947;2L GABA<sub>A</sub> receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (&#947;-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [<a href="">194</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Glycine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Joseph. W. Lynch Lucia G. Sivilotti Trevor G. Smart The inhibitory glycine receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Glycine Receptors</b>) is a member of the Cys-loop superfamily of transmitter-gated ion channels that includes the zinc activated channels, GABA<sub>A</sub>, nicotinic acetylcholine and 5-HT<sub>3</sub> receptors [<a href="">63</a>]. The receptor is expressed either as a homo-pentamer of &#945; subunits, or a complex now thought to harbour 2&#945; and 3&#946; subunits [<a href="">30</a>, <a href="">7</a>], that contain an intrinsic anion channel. Four differentially expressed isoforms of the &#945;-subunit (&#945;1-&#945;4) and one variant of the &#946;-subunit (&#946;1, <a href="!/hgnc_id/HGNC:4329"><i>GLRB</i></a>, <a href="">P48167</a>) have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for &#945;1 (&#945;1<sup>INS</sup> and &#945;1<sup>del</sup>), &#945;2 (&#945;2A and &#945;2B), &#945;3 (&#945;3S and &#945;3L) and &#946; (&#946;&#916;7) subunits and by mRNA editing of the &#945;2 and &#945;3 subunit [<a href="">80</a>, <a href="">91</a>, <a href="">18</a>]. Both &#945;2 splicing and &#945;3 mRNA editing can produce subunits (<i>i.e.</i>, &#945;2B and &#945;3P185L) with enhanced agonist sensitivity. Predominantly, the mature form of the receptor contains &#945;1 (or &#945;3) and &#946; subunits while the immature form is mostly composed of only &#945;2 subunits. RNA transcripts encoding the &#945;4-subunit have not been detected in adult humans. The N-terminal domain of the &#945;-subunit contains both the agonist and <a href= "">strychnine</a> binding sites that consist of several discontinuous regions of amino acids. Inclusion of the &#946;-subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The &#946;-subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. The latter is a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero-oligomeric receptors to the synapse [<a href="">86</a>, <a href="">51</a>, <a href="">53</a>]. G-protein &#946;&#947; subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop [<a href="">122</a>, <a href="">121</a>]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [<a href="">94</a>]. Intracellular Ca<sup>2+</sup> appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [<a href="">24</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Inwardly rectifying potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 John P. Adelman David E. Clapham Hiroshi Hibino Atsushi Inanobe Lily Y. Jan Andreas Karschin Yoshihiro Kubo Yoshihisa Kurachi Michel Lazdunski Takashi Miki Colin G. Nichols Lawrence G. Palmer Wade L. Pearson Henry Sackin Susumu Seino Paul A. Slesinger Stephen Tucker Carol A. Vandenberg The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (K<sub>ir</sub>2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (K<sub>ir</sub>3.x) and the ATP-sensitive K channels (K<sub>ir</sub>6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming &#945; subunits form tetramers, and heteromeric channels may be formed within subfamilies (<i>e.g.</i> K<sub>ir</sub>3.2 with K<sub>ir</sub>3.3). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Ionotropic glutamate receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:44+01:00 Bernhard Bettler Graham L. Collingridge Ray Dingledine Stephen F. Heinemann Michael Hollmann Juan Lerma David Lodge Mark Mayer Masayoshi Mishina Christophe Mulle Shigetada Nakanishi Richard Olsen Stephane Peineau John A. Peters Peter Seeburg Michael Spedding Jeffrey C. Watkins The ionotropic glutamate receptors comprise members of the NMDA (N-methyl-D-aspartate), AMPA (&#945;-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [<a href="">34</a>, <a href="">87</a>, <a href="">147</a>]. Receptor heterogeneity within each class arises from the homo-oligomeric, or hetero-oligomeric, assembly of distinct subunits into cation-selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), three transmembrane domains composed of three membrane spans (M1, M3 and M4), a channel lining re-entrant &#8216;p-loop&#8217; (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [<a href="">94</a>, <a href="">66</a>, <a href="">102</a>, <a href="">147</a>, <a href="">77</a>]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2 &#8211; see below) has recently been solved at 3.6&#197; resolution [<a href="">135</a>] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [<a href="">69</a>]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from [<a href="">34</a>, 65, <a href="">30</a>, <a href="">73</a>, <a href="">41</a>, <a href="">108</a>, <a href="">23</a>, <a href="">64</a>, <a href="">147</a>, <a href="">106</a>, <a href="">107</a>, <a href="">152</a>]. Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.<br><br><b>The classification of glutamate receptor subunits has been re-addressed by <u>NC-IUPHAR</u> [<a href="">27</a>]</b>. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.<br><br><b>NMDA receptors</b><br>NMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit [<a href="">40</a>, <a href="">24</a>]. The minimal requirement for efficient functional expression of NMDA receptors <i>in vitro</i> is a di-heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain [<a href="">47</a>, <a href="">94</a>, <a href="">69</a>]. However, more complex tri-heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generated<i> in vitro</i> and occur<i> in vivo</i>. The NMDA receptor channel commonly has a high relative permeability to Ca<sup>2+</sup> and is blocked, in a voltage-dependent manner, by Mg<sup>2+</sup> such that at resting potentials the response is substantially inhibited.<br><br><b>AMPA and Kainate receptors</b><br>AMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I (i.e. &#947;2, &#947;3, &#947;4 and &#947;8) act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology (reviewed in [<a href="">42</a>, <a href="">98</a>, <a href="">145</a>, <a href="">63</a>]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1-3 subunits are also capable of assembling into heterotetramers (<i>e.g</i>. GluK1/K2; [<a href="">82</a>, <a href="">113</a>, <a href="">112</a>]). Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for <a href= "">kainate</a>, but lack function, but can form heteromers when expressed with GluK1-3 subunits (<i>e.g</i>. GluK2/K5; reviewed in [<a href="">113</a>, <a href="">64</a>, <a href="">112</a>]). Kainate receptors may also exhibit &#8216;metabotropic&#8217; functions [<a href="">82</a>, <a href="">123</a>]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [<a href="">112</a>, <a href="">83</a>]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl- for their activation [<a href="">11</a>, <a href="">114</a>]. RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p-loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca<sup>2+</sup>; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and Joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [<a href="">131</a>, <a href="">62</a>]. GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit [<a href="">82</a>, <a href="">112</a>]. Native AMPA and kainate receptors displaying differential channel conductances, Ca<sup>2+</sup> permeabilites and sensitivity to block by intracellular polyamines have been identified [<a href="">29</a>, <a href="">62</a>, <a href="">86</a>]. GluA1-4 can exist as two variants generated by alternative splicing (termed &#8216;flip&#8217; and &#8216;flop&#8217;) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non-desensitized conformation of AMPA receptors and facilitate the action of <a href= "">cyclothiazide</a> [<a href="">98</a>]. Splice variants of GluK1-3 also exist which affects their trafficking [<a href="">82</a>, <a href="">112</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Nicotinic acetylcholine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Cecilia Gotti Michael. J. Marks Michael.Marks@Colorado.EDU Neil S. Millar Susan Wonnacott Nicotinic acetylcholine receptors are members of the Cys-loop family of transmitter-gated ion channels that includes the GABA<sub>A</sub>, strychnine-sensitive glycine and 5-HT<sub>3</sub> receptors [<a href="">210</a>, <a href="">3</a>, <a href="">155</a>, <a href="">220</a>, <a href="">252</a>]. All nicotinic receptors are pentamers in which each of the five subunits contains four &#945;-helical transmembrane domains. Genes encoding a total of 17 subunits (&#945;1-10, &#946;1-4, &#947;, &#948; and &#949;) have been identified [<a href="">117</a>]. All subunits with the exception of &#945;8 (present in avian species) have been identified in mammals. All &#945; subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named &#945; lack these residues [<a href="">155</a>]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the &#945; subunit (principal component), and three on the adjacent subunit (complementary component). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains [<a href="">257</a>, <a href="">85</a>]; see also [<a href="">103</a>]). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (<i>e.g.</i>[<a href="">33</a>]) and the crystal structure of the extracellular domain of the &#945;1 subunit bound to <a href= "">&#945;-bungarotoxin</a> at 1.94 &#197; resolution [<a href="">53</a>], has revealed the orthosteric binding site in detail (reviewed in [<a href="">210</a>, <a href="">117</a>, <a href="">37</a>, <a href="">193</a>]). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (&#945;1)<sub>2</sub>&#946;1&#948;&#949;, whereas an extrajunctional (&#945;1)<sub>2</sub>&#946;1&#947;&#948; receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of &#945;(2-6) and &beta(2-4) subunits. For &#945;2, &#945;3, &#945;4 and &#946;2 and &#946;4 subunits, pairwise combinations of &#945; and &#946; (<i>e.g.</i> &#945;3&#946;4 and &#945;4&#946;2) are sufficient to form a functional receptor <i>in vitro</i>, but far more complex isoforms may exist <i>in vivo</i> (reviewed in [<a href="">94</a>, <a href="">91</a>, <a href="">155</a>]). There is strong evidence that the pairwise assembly of some &#945; and &#946; subunits can occur with variable stoichiometry [<i>e.g.</i> (&#945;4)<sub>2</sub>(&#946;2)<sub>2</sub> or (&#945;4)<sub>3</sub>(&#946;2)<sub>2</sub>] which influences the biophysical and pharmacological properties of the receptor [<a href="">155</a>]. &#945;5 and &#946;3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another &#945; and &#946; pair [e.g. &#945;4&#945;5&#945;&#946;2, &#945;4&#945;&#946;2&#946;3, &#945;5&#945;6&#946;2, see [<a href="">155</a>] for further examples]. The &#945;6 subunit can form a functional receptor when co-expressed with &#946;4 <i>in vitro</i>, but more efficient expression ensues from incorporation of a third partner, such as &#946;3 [<a href="">256</a>]. The &#945;7, &#945;8, and &#945;9 subunits form functional homo-oligomers, but can also combine with a second subunit to constitute a hetero-oligomeric assembly (<i>e.g.</i> &#945;7&#946;2 and &#945;9&#945;10). For functional expression of the &#945;10 subunit, co-assembly with &#945;9 is necessary. The latter, along with the &#945;10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or <i>in vivo</i>, are given in [<a href="">155</a>]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by [<a href="">154</a>, <a href="">9</a>, <a href="">115</a>]).<br><br>The nicotinic receptor Subcommittee of <u><b>NC-IUPHAR</b></u> has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally- and/or heterologously-expressed nACh receptor subtypes [<a href="">139</a>]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant &#945; subunit contained in that receptor subtype. An asterisk following the indicated &#945; subunit denotes that other subunits are known to, or may, assemble with the indicated &#945; subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses &#8211; see also [<a href="">44</a>]). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## P2X receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Francesco Di Virgilio Richard J. Evans Simonetta Falzoni Michael F. Jarvis Charles Kennedy Baljit S. Khakh Brian King Patrizia Pellegatti John A. Peters P2X receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on P2X Receptors [<a href="">46</a>, <a href="">134</a>]</b>) have a trimeric topology [<a href="">118</a>, <a href="">132</a>, <a href="">177</a>] with two putative TM domains, gating primarily Na<sup>+</sup>, K<sup>+</sup> and Ca<sup>2+</sup>, exceptionally Cl<sup>-</sup>. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single receptor in order to activate it [<a href="">132</a>, <a href="">88</a>, <a href="">96</a>, <a href="">161</a>]. Native receptors may occur as either homotrimers (<i>e.g.</i> P2X1 in smooth muscle) or heterotrimers (<i>e.g.</i> P2X2:P2X3 in the nodose ganglion [<a href="">251</a>], P2X1:P2X5 in mouse cortical astrocytes [<a href="">146</a>], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [<a href="">50</a>, <a href="">207</a>]. P2X2, P2X4 and P2X7 receptors have been shown to form functional homopolymers which, in turn, activate pores permeable to low molecular weight solutes [<a href="">229</a>]. The hemi-channel pannexin-1 has been implicated in the pore formation induced by P2X7 [<a href="">188</a>], but not P2X2 [<a href="">38</a>], receptor activation. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Transient Receptor Potential channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Nathaniel T. Blair Ingrid Carvacho Dipayan Chaudhuri David E. Clapham Paul DeCaen Markus Delling Julia F. Doerner Lu Fan Kotdaji Ha Sven E. Jordt David Julius Kristopher T Kahle Boyi Liu David McKemy Bernd Nilius Elena Oancea Grzegorz Owsianik Antonio Riccio Rajan Sah; Stephanie C. Stotz Jinbin Tian Dan Tong Charlotte Van den Eynde Joris Vriens Long-Jun Wu Haoxing Xu Lixia Yue Xiaoli Zhang Michael X. Zhu <p>The TRP superfamily of channels (<b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">145</a>, <a href="">915</a>]</b>), whose founder member is the <i>Drosophila</i> Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative transmembrane domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [<a href="">630</a>]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [<a href="">344</a>, <a href="">589</a>, <a href="">979</a>, <a href="">216</a>]. The established, or potential, involvement of TRP channels in disease is reviewed in [<a href="">384</a>, <a href="">588</a>] and [<a href="">591</a>], together with a special edition of <i>Biochemica et Biophysica Acta</i> on the subject [<a href="">588</a>]. Additional disease related reviews, for pain [<a href="">542</a>], stroke [<a href="">967</a>], sensation and inflammation [<a href="">843</a>], itch [<a href="">109</a>], and airway disease [<a href="">261</a>, <a href="">896</a>], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [<a href="">692</a>]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P<sub>2 </sub> although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [<a href="">862</a>, <a href="">592</a>, <a href="">689</a>]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. </p><heading>TRPA (ankyrin) family</heading><p>TRPA1 is the sole mammalian member of this group (reviewed by [<a href="">246</a>]). TRPA1 activation of sensory neurons contribute to nociception [<a href="">356</a>, <a href="">763</a>, <a href="">516</a>]. Pungent chemicals such as mustard oil (AITC), <a href= "">allicin</a>, and <a href= "">cinnamaldehyde</a> activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [<a href="">491</a>, <a href="">47</a>, <a href="">311</a>, <a href="">493</a>]. Alkenals with &#945;, &#946;-unsaturated bonds, such as propenal (<a href= "">acrolein</a>), butenal (<a href= "">crotylaldehyde</a>), and <a href= "">2-pentenal</a> can react with free thiols <i>via</i> Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [<a href="">21</a>, <a href="">47</a>]. Covalent modification leads to sustained activation of TRPA1. Chemicals including <a href= "">carvacrol</a>, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [<a href="">364</a>, <a href="">438</a>, <a href="">923</a>, <a href="">922</a>]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [<a href="">365</a>, <a href="">175</a>]. The electron cryo-EM structure of TRPA1 [<a href="">639</a>] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short &#8216;pore helices&#8217; pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca<sup>2+</sup> ions. </p><heading>TRPC (canonical) family</heading><p>Members of the TRPC subfamily (reviewed by [<a href="">239</a>, <a href="">673</a>, <a href="">14</a>, <a href="">4</a>, <a href="">79</a>, <a href="">382</a>, <a href="">638</a>, <a href="">55</a>]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of G<sub>q/11</sub>-coupled receptors, or receptor tyrosine kinases (reviewed by [<a href="">661</a>, <a href="">814</a>, <a href="">915</a>]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [<a href="">4</a>]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [<a href="">14</a>] and [<a href="">383</a>]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [<a href="">640</a>, <a href="">14</a>, <a href="">665</a>, <a href="">703</a>, <a href="">954</a>, <a href="">132</a>, <a href="">626</a>, <a href="">51</a>, <a href="">133</a>]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by <a href= "">2-APB</a> and <a href= "">SKF96365</a> [<a href="">295</a>, <a href="">294</a>]. Activation of TRPC channels by lipids is discussed by [<a href="">55</a>]. Important progress has been recently made in TRPC pharmacology [<a href="">692</a>, <a href="">529</a>, <a href="">372</a>, <a href="">87</a>]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [<a href="">248</a>, <a href="">56</a>, <a href="">759</a>, <a href="">879</a>]. <br><br><b>TRPC1/C4/C5 subgroup</b><br> TRPC1 alone may not form a functional ion channel [<a href="">191</a>]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La<sup>3+</sup>. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [<a href="">951</a>, <a href="">625</a>, <a href="">624</a>, <a href="">952</a>, 462, <a href="">988</a>, <a href="">947</a>].<br><br><b>TRPC3/C6/C7 subgroup</b><br> All members are activated by diacylglycerol independent of protein kinase C stimulation [<a href="">295</a>].</p><heading>TRPM (melastatin) family</heading><p>Members of the TRPM subfamily (reviewed by [<a href="">230</a>, <a href="">294</a>, <a href="">640</a>, <a href="">978</a>]) fall into the five subgroups outlined below. <br><br><b>TRPM1/M3 subgroup</b><br>In darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [<a href="">341</a>, <a href="">609</a>]. TRPM3 (reviewed by [<a href="">615</a>]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [<a href="">803</a>]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [<a href="">614</a>, <a href="">802</a>]. TRPM3 may contribute to the detection of noxious heat [<a href="">870</a>].<br><br><b>TRPM2</b><br>TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells) and ischemic conditions. However, the direct activators are ADPR(P) and calcium. As for many ion channels, PIP<sub>2</sub> must also be present (reviewed by [<a href="">935</a>]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [<a href="">200</a>]. The C-terminal domain contains a TRP motif, a coiled-coil region, and an enzymatic NUDT9 homologous domain. TRPM2 appears not to be activated by NAD, NAAD, or NAADP, but is directly activated by ADPRP (adenosine-5'-O-disphosphoribose phosphate) [<a href="">827</a>]. TRPM2 is involved in warmth sensation [<a href="">724</a>], and contributes to neurological diseases [<a href="">61</a>]. Recent study shows that 2'-deoxy-ADPR is an endogenous TRPM2 superagonist [<a href="">231</a>]. <br><br><b>TRPM4/5 subgroup</b><br>TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca<sup>2+</sup> [<a href="">915</a>]. A splice variant of TRPM4 (<i>i.e.</i>TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [<a href="">278</a>]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [<a href="">507</a>]. Mutations are associated with conduction defects [<a href="">347</a>, <a href="">507</a>, <a href="">753</a>]. TRPM4 has been shown to be an important regulator of Ca<sup>2+</sup> entry in to mast cells [<a href="">847</a>] and dendritic cell migration [<a href="">39</a>]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [<a href="">460</a>] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [<a href="">439</a>]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [<a href="">206</a>].<br><br><b>TRPM6/7 subgroup</b><br>TRPM6 and 7 combine channel and enzymatic activities (&#8216;chanzymes&#8217;). These channels have the unusual property of permeation by divalent (Ca<sup>2+</sup>, Mg<sup>2+</sup>, Zn<sup>2+</sup>) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg<sup>2+</sup> at ~0.6 mM, around the free level of Mg<sup>2+</sup> in cells. Whether they contribute to Mg<sup>2+</sup> homeostasis is a contentious issue. When either gene is deleted in mice, the result is embryonic lethality. The C-terminal kinase region is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones. TRPM7 is responsible for oxidant- induced Zn<sup>2+</sup> release from intracellular vesicles [<a href="">3</a>] and contributes to intestinal mineral absorption essential for postnatal survival [<a href="">532</a>]. <br><br><b>TRPM8</b><br>Is a channel activated by cooling and pharmacological agents evoking a &#8216;cool&#8217; sensation and participates in the thermosensation of cold temperatures [<a href="">50</a>, <a href="">147</a>, <a href="">186</a>] reviewed by [<a href="">864</a>, <a href="">481</a>, <a href="">391</a>, <a href="">556</a>]. </p><heading>TRPML (mucolipin) family</heading><p>The TRPML family [<a href="">676</a>, <a href="">964</a>, <a href="">670</a>, <a href="">926</a>, <a href="">156</a>] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (<i>MCOLN1</i>) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [<a href="">704</a>]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [<a href="">270</a>]. A naturally occurring gain of function mutation in TRPML3 (<i>i.e.</i> A419P) results in the varitint waddler (V<i>a</i>) mouse phenotype (reviewed by [<a href="">676</a>, <a href="">593</a>]). </p><heading>TRPP (polycystin) family</heading><p>The TRPP family (reviewed by [<a href="">179</a>, <a href="">177</a>, <a href="">252</a>, <a href="">905</a>, <a href="">320</a>]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [<a href="">915</a>]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [<a href="">293</a>]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [<a href="">775</a>]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. </p><heading>TRPV (vanilloid) family</heading><p>Members of the TRPV family (reviewed by [<a href="">849</a>]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6.<br><br><b>TRPV1-V4 subfamily</b><br>TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [<a href="">660</a>, <a href="">756</a>, <a href="">786</a>]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [<a href="">722</a>]. The pharmacology of TRPV1 channels is discussed in detail in [<a href="">280</a>] and [<a href="">868</a>]. TRPV2 is probably not a thermosensor in man [<a href="">635</a>], but has recently been implicated in innate immunity [<a href="">469</a>]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [<a href="">106</a>, <a href="">454</a>].<br><br><b>TRPV5/V6 subfamily</b><br> TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [<a href="">901</a>, <a href="">168</a>, <a href="">558</a>, <a href="">227</a>]).</p> 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Two P domain potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Douglas A. Bayliss Gábor Czirják Péter Enyedi Steve A.N. Goldstein Florian Lesage Daniel L. Minor, Jr. Leigh D. Plant Francisco Sepúlveda Brenda T. Winn The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming &#945;-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K<sub>2P</sub> channels (and not two-pore channels). Some of the K<sub>2P</sub> subunits can form heterodimers across subfamilies (<i>e.g.</i> K<sub>2P</sub>3.1 with K<sub>2P</sub>9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the <a href="FamilyIntroductionForward?familyId=79">More detailed introduction</a>, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated calcium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 William A. Catterall Edward Perez-Reyes Terrance P. Snutch Jörg Striessnig Calcium (Ca<sup>2+</sup>) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca<sup>2+</sup>channels was proposed by [<a href="">110</a>] and <b>approved by the <u>NC-IUPHAR</u> Subcommittee on Ca<sup>2+</sup> channels [<a href="">60</a>]</b>. Ca<sup>2+</sup> channels form hetero-oligomeric complexes. The &#945;1 subunit is pore-forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned &#945;1-subunits can be grouped into three families: (1) the high-voltage activated dihydropyridine-sensitive (L-type, Ca<sub>V</sub>1.x) channels; (2) the high-voltage activated dihydropyridine-insensitive (Ca<sub>V</sub>2.x) channels and (3) the low-voltage-activated (T-type, Ca<sub>V</sub>3.x) channels. Each &#945;1 subunit has four homologous repeats (I&#8211;IV), each repeat having six transmembrane domains and a pore-forming region between transmembrane domains S5 and S6. Gating is thought to be associated with the membrane-spanning S4 segment, which contains highly conserved positive charges. Many of the &#945;1-subunit genes give rise to alternatively spliced products. At least for high-voltage activated channels, it is likely that native channels comprise co-assemblies of &#945;1, &#946; and &#945;2&#8211;&#948; subunits. The &#947; subunits have not been proven to associate with channels other than the &#945;1s skeletal muscle Cav1.1 channel. The &#945;2&#8211;&#948;1 and &#945;2&#8211;&#948;2 subunits bind <a href= "">gabapentin</a> and <a href= "">pregabalin</a>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Bernard Attali K. George Chandy M. Hunter Giese Stephan Grissmer George A. Gutman GAGutman@UCI.Edu Lily Y. Jan Michel Lazdunski David Mckinnon Jeanne Nerbonne Luis A. Pardo Gail A. Robertson Bernardo Rudy Michael C. Sanguinetti Walter Stühmer James S. Trimmer Xiaoliang Wang The 6TM family of K channels comprises the voltage-gated K<sub>V </sub>subfamilies, the EAG subfamily (which includes hERG channels), the Ca<sup>2+</sup>-activated Slo subfamily (actually with 7TM, termed BK) and the Ca<sup>2+</sup>-activated SK subfamily. These channels possess a pore-forming &#945; subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. K<sub>v</sub>1.1 with K<sub>v</sub>1.2; K<sub>v</sub>7.2 with K<sub>v</sub>7.3). The pharmacology largely reflects the subunit composition of the functional channel. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated sodium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 William A. Catterall Alan L. Goldin Stephen G. Waxman Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming &#945; subunit, which may be associated with either one or two &#946; subunits [<a href="">176</a>]. &#945;-Subunits consist of four homologous domains (I&#8211;IV), each containing six transmembrane segments (S1&#8211;S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [<a href="">268</a>]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [<a href="">268</a>]. Auxiliary &#946;1, &#946;2, &#946;3 and &#946;4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.<br><br><b>The nomenclature for sodium channels was proposed by Goldin <i>et al</i>., (2000) [<a href="">143</a>] and approved by the <u>NC-IUPHAR</u> Subcommittee on sodium channels (Catterall <i>et al</i>., 2005, [<a href="">51</a>]).</b> 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ZAC (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Paul Davies Tim G. Hales Anders A. Jensen John A. Peters The zinc-activated channel (ZAC, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee for the Zinc Activated Channel</b>) is a member of the Cys-loop family that includes the nicotinic ACh, 5-HT<sub>3</sub>, GABA<sub>A</sub> and strychnine-sensitive glycine receptors [<a href="">1</a>, <a href="">2</a>, <a href="">3</a>]. The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na<sup>+</sup>, K<sup>+</sup> and Cs<sup>+</sup>, but impermeable to Ca<sup>2+</sup> and Mg<sup>2+</sup> [<a href="">3</a>]. ZAC displays constitutive activity that can be blocked by <a href= "">tubocurarine</a> and high concentrations of Ca<sup>2+</sup> [<a href="">3</a>]. Although denoted ZAC, the channel is more potently activated by protons and copper, with greater and lesser efficacy than zinc, respectively [<a href="">3</a>]. ZAC is present in the human, chimpanzee, dog, cow and opossum genomes, but is functionally absent from mouse, or rat, genomes [<a href="">1</a>, <a href="">2</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 1A. Thyroid hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Douglas Forrest Anthony N. Hollenberg Paul Webb Thyroid hormone receptors (<b>TRs, nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">10</a>]</b>) are nuclear hormone receptors of the NR1A family, with diverse roles regulating macronutrient metabolism, cognition and cardiovascular homeostasis. TRs are activated by thyroxine (<a href= "">T<sub>4</sub></a>) and thyroid hormone (<a href= "">triiodothyronine</a>). Once activated by a ligand, the receptor acts as a transcription factor either as a monomer, homodimer or heterodimer with members of the retinoid X receptor family. <a href= "">NH-3</a> has been described as an antagonist at TRs with modest selectivity for TR&#946; [<a href="">38</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 1F. Retinoic acid-related orphans (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Anton Jetten Hong Soon Kang Yukimasa Takeda Retinoic acid receptor-related orphan receptors (ROR, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">10</a>]</b>) have yet to be assigned a de&#64257;nitive endogenous ligand, although ROR&#945; may be synthesized with a &#8216;captured&#8217; agonist such as <a href= "">cholesterol</a> [<a href="">63</a>, <a href="">62</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 1H. Liver X receptor-like receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Donald P. McDonnell Rachid Safi Liver X and farnesoid X receptors (LXR and FXR, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">68</a>]</b>) are members of a steroid analogue-activated nuclear receptor subfamily, which form heterodimers with members of the retinoid X receptor family. Endogenous ligands for LXRs include hydroxycholesterols (OHC), while FXRs appear to be activated by bile acids. In humans and primates, <i>NR1H5P</i> is a pseudogene. However, in other mammals, it encodes a functional nuclear hormone receptor that appears to be involved in cholesterol biosynthesis [<a href="">71</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 1I. Vitamin D receptor-like receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Sylvia Christakos Vitamin D (VDR), Pregnane X (PXR) and Constitutive Androstane (CAR) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">47</a>]</b>) are members of the NR1I family of nuclear receptors, which form heterodimers with members of the retinoid X receptor family. PXR and CAR are activated by a range of exogenous compounds, with no established endogenous physiological agonists, although high concentrations of bile acids and bile pigments activate PXR and CAR [<a href="">47</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 2A. Hepatocyte nuclear factor-4 receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Frances M. Sladek The nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the <b><u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">8</a>]</b>. While linoleic acid has been identified as the endogenous ligand for HNF4&#945; its function remains ambiguous [<a href="">73</a>]. HNF4&#947; has yet to be paired with an endogenous ligand. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 2F. COUP-TF-like receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:43+01:00 Ming-Jer Tsai Sophia Y. Tsai COUP-TF-like receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">6</a>]</b>) have yet to be officially paired with an endogenous ligand. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 3A. Estrogen receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Laurel Coons Kenneth S. Korach Estrogen receptor (ER) activity regulates diverse physiological processes <i>via</i> transcriptional modulation of target genes. The selection of target genes and the magnitude of the response, be it induction or repression, are determined by many factors, including the effect of the hormone ligand and DNA binding on ER structural conformation, and the local cellular regulatory environment. The cellular environment defines the specific complement of DNA enhancer and promoter elements present and the availability of coregulators to form functional transcription complexes. Together, these determinants control the resulting biological response. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## 3C. 3-Ketosteroid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Derek Cain John Cidlowski Dean P. Edwards Peter Fuller Sandra L. Grimm Sean Hartig Carol A. Lange Robert H. Oakley Jennifer K. Richer Carol A. Sartorius Marc Tetel Nancy Weigel Morag Young Steroid hormone receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">65</a>, <a href="">193</a>]</b>) are nuclear hormone receptors of the NR3 class, with endogenous agonists that may be divided into 3-hydroxysteroids (<a href= "">estrone</a> and <a href= "">17&#946;-estradiol</a>) and 3-ketosteroids (<a href= "">dihydrotestosterone</a> [DHT], <a href= "">aldosterone</a>, <a href= "">cortisol</a>, <a href= "">corticosterone</a>, <a href= "">progesterone</a> and <a href= "">testosterone</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Lanosterol biosynthesis pathway (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Helen E. Benson Lanosterol is a precursor for cholesterol, which is synthesized primarily in the liver in a pathway often described as the mevalonate or HMG-CoA reductase pathway. The first two steps (formation of <a href= "">acetoacetyl CoA</a> and the mitochondrial generation of <a href= "">(S)-3-hydroxy-3-methylglutaryl-CoA</a>) are also associated with oxidation of fatty acids. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Stephen P.H. Alexander Andrew J. Irving GPR18, GPR55 and GPR119 (<b>provisional nomenclature</b>), although showing little structural similarity to CB<sub>1</sub> and CB<sub>2</sub> cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [<a href="">98</a>]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated <i>in vitro</i> by <a href= "">N-arachidonoylglycine</a>, <a href= "">lysophosphatidylinositol</a> and <a href= "">N-oleoylethanolamide</a>, respectively, there is a lack of evidence for activation by these lipid messengers <i>in vivo</i>. As such, therefore, these receptors retain their orphan status. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Acid-sensing (proton-gated) ion channels (ASICs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Stephan Kellenberger Lachlan D. Rash Laurent Schild Acid-sensing ion channels (ASICs, <b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">35</a>]</b>) are members of a Na<sup>+</sup> channel superfamily that includes the epithelial Na<sup>+</sup> channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of <i>Caenorhabitis elegans</i>, channels in <i>Drosophila melanogaster</i> and 'orphan' channels that include BLINaC [<a href="">46</a>] and INaC [<a href="">47</a>] that have also been named BASICs, for bile acid-activated ion channels [<a href="">58</a>]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [<a href="">34</a>, <a href="">31</a>, <a href="">5</a>] to form proton-gated, voltage-insensitive, Na<sup>+</sup> permeable, channels (reviewed in [<a href="">33</a>, <a href="">57</a>]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASIC&#945;, BNaC2&#945;) [<a href="">55</a>], ASIC1b (ASIC&#946;, BNaC2&#946;) [<a href="">13</a>] and ASIC1b2 (ASIC&#946;2) [<a href="">50</a>]; note that ASIC1a is also permeable to Ca<sup>2+</sup>] and ASIC2 [termed ASIC2a (MDEG1, BNaC1&#945;, BNC1&#945;) [<a href="">45</a>, <a href="">56</a>, <a href="">30</a>] and ASIC2b (MDEG2, BNaC1&#946;) [<a href="">40</a>]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H<sup>+</sup>-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [<a href="">54</a>], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton-gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 [<a href="">1</a>, <a href="">32</a>, <a href="">24</a>, <a href="">39</a>]. ASIC channels are primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [<a href="">25</a>, <a href="">36</a>, <a href="">63</a>], responses to focal ischemia [<a href="">59</a>] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [<a href="">29</a>], as well as seizures [<a href="">64</a>] and pain [<a href="">19</a>, <a href="">20</a>, <a href="">10</a>, <a href="">22</a>]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [<a href="">40</a>, <a href="">3</a>, <a href="">28</a>, <a href="">8</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Aquaporins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Alex C. Conner Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [<a href="">9</a>]. Since the isolation and cloning of the first aquaporin (AQP1) [<a href="">10</a>], 12 additional mammalian members of the family have been identified, although little is known about the functional properties of one of these (<a href="!/hgnc_id/HGNC:19941" target="_blank"><i>AQP12A</i></a>; <a href="" target="_blank">Q8IXF9</a>) and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins (AQP0,-1,-2,-4,-5, -6 and -8) permeable mainly to water, but for some additional solutes [<a href="">2</a>]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [<a href="">8</a>], and superaquaporins (AQP11 and 12) located within cells [<a href="">5</a>]. Some aquaporins also conduct ammonia and/or H<sub>2</sub>O<sub>2</sub> giving rise to the terms 'ammoniaporins' ('aquaammoniaporins') and 'peroxiporins', respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1 [<a href="">8</a>]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [13]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia and loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman <i>et al</i>. (2014) [<a href="">12</a>], Kitchen <i>et al.</i> (2105) [<a href="">8</a>]].<br><br> Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six transmembrane helices and two half helices that constitute a seventh 'pseudotransmembrane domain' that surrounds a narrow water conducting channel [<a href="">9</a>]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [<a href="">9</a>] that may mediate the transport of gases (<i>e.g.</i> O<sub>2</sub>, CO<sub>2</sub>, NO) and cations (the central pore is the proposed transport pathway for cations through AQP1) by some AQPs [<a href="">4</a>, <a href="">6</a>]. Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from <i>Xenopus</i> oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [<a href="">3</a>] and they are therefore excluded from the tables [see Tradtrantip <i>et al.</i> (2017) [<a href="">11</a>] for a review]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Epithelial sodium channel (ENaC) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Israel Hanukoglu The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the distal kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon and some other organs [<a href="">20</a>, <a href="">11</a>, <a href="">7</a>]. In these epithelia, ENaC allows flow of Na<sup>+</sup> ions from the extracellular fluid in the lumen into the epithelial cell. Na<sup>+</sup> ions are then pumped out of the cytoplasm into the interstitial fluid by the Na<sup>+</sup>/K<sup>+</sup> ATPase located on the basolateral membrane [<a href="">39</a>]. As Na<sup>+</sup> is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na<sup>+</sup> flow is accompanied by a flow of water accompanying Na<sup>+</sup> ions [<a href="">6</a>]. Thus, ENaC has a central role in the regulation of ECF volume and blood pressure, especially via its function in the kidney [<a href="">25</a>, <a href="">30</a>]. The expression of ENaC subunits, hence its activity, is regulated by the renin-angotensin-aldosterone system, and other factors that are involved in electrolyte homeostasis [<a href="">30</a>, <a href="">1</a>, <a href="">29</a>]. In the respiratory tract and female reproductive tract large segments of the tracts are covered by multi-ciliated cells. In these cells ENaC has been shown to be located along the entire length of the cilia [<a href="">14</a>]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [<a href="">14</a>]. In contrast to ENaC, CFTR that is defective in cystic fibrosis is not located on non-cilial cell-surface [<a href="">14</a>]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation and cell migration [<a href="">14</a>, <a href="">33</a>]. ENaC has been recently localized in the germinal epithelium of the testis, Sertoli cells, spermatozoa, along the epididymis ducts, and smooth muscle cells [<a href="">35</a>, <a href="">36</a>]. Evidence has been provided that rare mutations in ENaC are associated with female infertility [<a href="">5</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Lysophospholipid (S1P) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Victoria Blaho Jerold Chun Deepa Jonnalagadda Yasuyuki Kihara Hirotaka Mizuno Chido Mpamhanga Sarah Spiegel Valerie Tan Sphingosine 1-phosphate (S1P) receptors (<b>nomenclature as agreed by the <u> NC-IUPHAR</u> Subcommittee on Lysophospholipid receptors [<a href="">70</a>]</b>) are activated by the endogenous lipid <a href= "">sphingosine 1-phosphate</a> (S1P). Originally cloned as orphan members of the endothelial differentiation gene (<i>edg</i>) family, current gene names have been designated as S1P<sub>1</sub>R through S1P<sub>5</sub>R [<a href="">52</a>]. S1PRs, particularly S1P<sub>1</sub>, are expressed throughout all mammalian organ systems. Ligand delivery occurs <i>via</i> two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P<sub>1</sub> in multiple cell types [<a href="">15</a>, <a href="">39</a>]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report <i>in vivo</i> S1P1R activation [<a href="">74</a>, <a href="">76</a>]. A crystal structure of an S1P<sub>1</sub>-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [<a href="">48</a>, <a href="">14</a>]. <a href= "">fingolimod</a> (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [<a href="">26</a>]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, <i>e.g.</i>, immune and nervous systems, although the precise nature of their receptor interactions requires clarification [<a href="">107</a>, <a href="">28</a>, <a href="">43</a>, <a href="">44</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC1 family of amino acid transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Philip M. Beart The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [<a href="">1</a>, <a href="">49</a>, <a href="">36</a>, <a href="">37</a>, <a href="">7</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Yoshikatsu Kanai The SLC3 and SLC7 families combine to generate functional transporters, where the subunit composition is a disulphide-linked combination of a heavy chain (SLC3 family) with a light chain (SLC7 family). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC6 neurotransmitter transporter family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:42+01:00 Stefan Bröer Gary Rudnick Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [<a href="">29</a>, <a href="">22</a>, <a href="">70</a>] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, <a href= "">GABA</a>, <a href= "">glycine</a> and neutral amino acids, plus the related bacterial NSS transporters [<a href="">99</a>]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuT<sub>Aa</sub>, a Na<sup>+</sup>-dependent amino acid transporter from <i>Aquiflex aeolicus</i> [<a href="">126</a>] and in several other transporter families structurally related to LeuT [<a href="">45</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC22 family of organic cation and anion transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Bruno Hagenbuch The SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine, playing a major role in drug disposition. The family may be divided into three subfamilies based on the nature of the substrate transported: organic cations (OCTs), organic anions (OATs) and organic zwiterrion/cations (OCTN). Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC28 and SLC29 families of nucleoside transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 James R. Hammond Nucleoside transporters are divided into two families, the sodium-dependent, concentrative solute carrier family 28 (SLC28) and the equilibrative, solute carrier family 29 (SLC29). The endogenous substrates are typically nucleosides, although some family members can also transport nucleobases and organic cations. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ABCA subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Mary Vore To date, 12 members of the human ABCA subfamily are identified. They share a high degree of sequence conservation and have been mostly related with lipid trafficking in a wide range of body locations. Mutations in some of these genes have been described to cause severe hereditary diseases related with lipid transport, such as fatal surfactant deficiency or harlequin ichthyosis. In addition, most of them are hypothesized to participate in the subcellular sequestration of drugs, thereby being responsible for the resistance of several carcinoma cell lines against drug treatment [<a href="">1</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ABCB subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Mary Vore The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [<a href="">4</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ABCC subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Mary Vore Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction [<a href="">5</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ABCD subfamily of peroxisomal ABC transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Stephan Kemp Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for the oxidation of a wide variety of metabolites, which include: saturated, monounsaturated and polyunsaturated fatty acids, branched-chain fatty acids, bile acids and dicarboxylic acids [<a href="">3</a>]. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. The mammalian peroxisomal membrane harbours three ATP-binding cassette (ABC) half-transporters, which act as homo- and/or heterodimers to transport these metabolites across the peroxisomal membrane. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## ABCG subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Ian Kerr This family of 'half-transporters' act as homo- or heterodimers; particularly ABCG5 and ABCG8 are thought to be obligate heterodimers. The ABCG5/ABCG heterodimer sterol transporter structure has been determined [<a href="">4</a>], suggesting an extensive intracellular nucleotide binding domain linked to the transmembrane domains by a fold in the primary sequence. The functional ABCG2 transporter appears to be a homodimer with structural similarities to the ABCG5/ABCG8 heterodimer [<a href="">7</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC8 family of sodium/calcium exchangers (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Jules Hancox The sodium/calcium exchangers (NCX) use the extracellular sodium concentration to facilitate the extrusion of calcium out of the cell. Alongside the plasma membrane Ca<sup>2+</sup>-ATPase (<a href="FamilyDisplayForward?familyId=138#159_overview">PMCA</a>) and sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (<a href="FamilyDisplayForward?familyId=138">SERCA</a>), as well as the sodium/potassium/calcium exchangers (NKCX, <a href="FamilyDisplayForward?familyId=202">SLC24 family</a>), NCX allow recovery of intracellular calcium back to basal levels after cellular stimulation. When intracellular sodium ion levels rise, for example, following depolarisation, these transporters can operate in the reverse direction to allow calcium influx and sodium efflux, as an electrogenic mechanism. Structural modelling suggests the presence of 9 TM segments, with a large intracellular loop between the fifth and sixth TM segments. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC14 family of facilitative urea transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Gavin Stewart As a product of protein catabolism, urea is moved around the body and through the kidneys for excretion. Although there is experimental evidence for concentrative urea transporters, these have not been defined at the molecular level. The SLC14 family are facilitative transporters, allowing <a href= "">urea</a> movement down its concentration gradient. Multiple splice variants of these transporters have been identified; for UT-A transporters, in particular, there is evidence for cell-specific expression of these variants with functional impact [<a href="">3</a>]. Topographical modelling suggests that the majority of the variants of SLC14 transporters have 10 TM domains, with a glycosylated extracellular loop at TM5/6, and intracellular C- and N-termini. The UT-A1 splice variant, exceptionally, has 20 TM domains, equivalent to a combination of the UT-A2 and UT-A3 splice variants. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC15 family of peptide transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 David T. Thwaites Tiziano Verri The Solute Carrier 15 (SLC15) family of peptide transporters, alias H<sup>+</sup>-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di- and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC23 family of ascorbic acid transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 James M. May Predicted to be 12 TM segment proteins, members of this family transport the reduced form of ascorbic acid (while the oxidized form may be handled by members of the <a href="FamilyDisplayForward?familyId=140">SLC2 family</a> (GLUT1/SLC2A1, GLUT3/SLC2A3 and GLUT4/SLC2A4). <a href= "">phloretin</a> is considered a non-selective inhibitor of these transporters, with an affinity in the micromolar range. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC27 family of fatty acid transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Andreas Stahl Fatty acid transporter proteins (FATPs) are a family (SLC27) of six transporters (FATP1-6). They have at least one, and possibly six [<a href="">4</a>, <a href="">11</a>], transmembrane segments, and are predicted on the basis of structural similarities to form dimers. SLC27 members have several structural domains: integral membrane associated domain, peripheral membrane associated domain, FATP signature, intracellular AMP binding motif, dimerization domain, lipocalin motif, and an ER localization domain (identified in FATP4 only) [<a href="">2</a>, <a href="">8</a>, <a href="">9</a>]. These transporters are unusual in that they appear to express intrinsic very long-chain acyl-CoA synthetase (<a href="">EC 6.2.1.-</a> , <a href="">EC</a>) enzyme activity. Within the cell, these transporters may associate with plasma and peroxisomal membranes. FATP1-4 and -6 transport long- and very long-chain fatty acids, while FATP5 transports long-chain fatty acids as well as bile acids [<a href="">7</a>, <a href="">11</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC36 family of proton-coupled amino acid transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Catriona M.H. Anderson David T. Thwaites Members of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma-membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [3]. In lysosomes, PAT1 functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [<a href="">2</a>, <a href="">15</a>]. PAT2 is expressed at the apical membrane of the renal proximal tubule [<a href="">5</a>] and at the plasma-membrane in brown/beige adipocytes [<a href="">17</a>]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [<a href="">8</a>]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC47 family of multidrug and toxin extrusion transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Ken-ichi Inui These proton:organic cation exchangers are predicted to have 13 TM segments [<a href="">10</a>] and are suggested to be responsible for excretion of many drugs in the liver and kidneys. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLCO family of organic anion transporting polypeptides (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:41+01:00 Bruno Hagenbuch The SLCO superfamily is comprised of the organic anion transporting polypeptides (OATPs). The 11 human OATPs are divided into 6 families and ten subfamilies based on amino acid identity. These proteins are located on the plasma membrane of cells throughout the body. They have 12 TM domains and intracellular termini, with multiple putative glycosylation sites. OATPs mediate the sodium-independent uptake of a wide range of amphiphilic substrates, including many drugs and toxins. Due to the multispecificity of these proteins, this guide lists classes of substrates and inhibitors for each family member. More comprehensive lists of substrates, inhibitors, and their relative affinities may be found in the review articles listed below. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Cytochrome P450 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Kathryn Burns Nuala Ann Helsby The cytochrome P450 enzyme family (CYP450), E.C. 1.14.-.-, were originally defined by their strong absorbance at 450 nm due to the reduced carbon monoxide-complexed haem component of the cytochromes. They are an extensive family of haem-containing monooxygenases with a huge range of both endogenous and exogenous substrates. These include sterols, fat-soluble vitamins, pesticides and carcinogens as well as drugs. The substrates of some orphan CYP are not known. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologue may not catalyse the metabolism of the same substrates. Although the majority of CYP450 enzyme activities are concentrated in the liver, the extrahepatic enzyme activities also contribute to patho/physiological processes. Genetic variation of CYP450 isoforms is widespread and likely underlies a significant proportion of the individual variation to drug administration. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Adenosine turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Detlev Boison A multifunctional, ubiquitous molecule, <a href= "">adenosine</a> acts at cell-surface G protein-coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto-5&#8217;-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism <i>via </i>adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, <i>via </i>adenosine deaminase or adenosine kinase (requiring <a href= "">ATP</a> as co-substrate). Intracellular adenosine may be produced by cytosolic 5&#8217;-nucleotidases or through S-adenosylhomocysteine hydrolase (also producing <a href= "">L-homocysteine</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Nitric oxide synthases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Timothy R. Billiar Giuseppe Cirino David Fulton Roberto Motterlini Andreas Papapetropoulos Csaba Szabo Nitric oxide synthases (NOS, <a href="">E.C.</a>) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of <a href= "">L-arginine</a> with the resultant by-product, <a href= "">L-citrulline</a>. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post-translation mechanisms regulating enzyme activity. The nomenclature suggested by <b>NC-IUPHAR </b>of NOS I, II and III [<a href="">11</a>] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C-terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4-dependent reduction of heme bound oxygen for insertion into the substrate, L-arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca<sup>2+</sup>/<a href= "">calmodulin</a> with great avidity and is essentially calcium-independent and constitutively active. Efficient stimulus-dependent coupling of nNOS and eNOS is achieved <i>via</i> subcellular targeting through respective N-terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. <a href= "">L-NAME</a> and related modified arginine analogues are inhibitors of all three isoforms, with IC<sub>50</sub> values in the micromolar range. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Adenylyl cyclases (ACs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-24T11:46:34+01:00 Carmen W. Dessauer Rennolds Ostrom Roland Seifert Val J. Watts <p>Adenylyl cyclase, <a href=";search_string=">E.C.</a>, converts <a href="">ATP</a> to <a href="">cyclic AMP</a> and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (<strong>nomenclature as approved by the <u>NC-IUPHAR</u> Subcommittee on Adenylyl cyclases</strong> [<a href="">9</a>]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gα<sub>s</sub> (the stimulatory G protein α subunit) and <a href="">forskolin</a> (except AC9, [<a href="">21</a>]). <a href="">adenosine</a> and its derivatives (<em>e.g.</em> <a href="">2',5'-dideoxyadenosine</a>), acting through the P-site,are inhibitors of adenylyl cyclase activity [<a href="">27</a>]. Four families of membranous adenylyl cyclase are distinguishable: <a href="">calmodulin</a>-stimulated (AC1, AC3 and AC8), Ca<sup>2+</sup>- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca<sup>2+</sup>-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [<a href="">5</a>].</p> 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Chen Yan 3',5'-Cyclic nucleotide phosphodiesterases (PDEs, 3',5'-cyclic-nucleotide 5'-nucleotidohydrolase), <a href="">E.C.</a>, catalyse the hydrolysis of a 3',5'-cyclic nucleotide (usually <a href= "">cyclic AMP</a> or <a href= "">cyclic GMP</a>). <a href= "">isobutylmethylxanthine</a> is a nonselective inhibitor with an IC<sub>50</sub> value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2',3'-cyclic nucleotide 3'-phosphodiesterase (<a href="">E.C.</a> CNPase) activity is associated with myelin formation in the development of the CNS. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Cyclooxygenase (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Angelo A. Izzo Jane A. Mitchell Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate,hydrogen-donor : oxygen oxidoreductase) activity, catalyses the formation of <a href= "">PGG<sub>2</sub></a> from <a href= "">arachidonic acid</a>. Hydroperoxidase activity inherent in the enzyme catalyses the formation of <a href= "">PGH<sub>2</sub></a> from <a href= "">PGG<sub>2</sub></a>. COX-1 and -2 can be nonselectively inhibited by <a href= "">ibuprofen</a>, <a href= "">ketoprofen</a>, <a href= "">naproxen</a>, <a href= "">indomethacin</a> and <a href= "">paracetamol</a> (acetaminophen). PGH<sub>2</sub> may then be metabolised to prostaglandins and thromboxanes by various prostaglandin synthases in an apparently tissue-dependent manner. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Haem oxygenase (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Timothy R. Billiar Giuseppe Cirino David Fulton Roberto Motterlini Andreas Papapetropoulos Csaba Szabo Haem oxygenase (heme,hydrogen-donor:oxygen oxidoreductase (&#945;-methene-oxidizing, hydroxylating)), <a href="">E.C.</a>, converts <a href= "">heme</a> into <a href= "">biliverdin</a> and carbon monoxide, utilizing <a href= "">NADPH</a> as cofactor. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Hydrogen sulphide synthesis (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Timothy R. Billiar Giuseppe Cirino David Fulton Roberto Motterlini Andreas Papapetropoulos Csaba Szabo Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (H<sub>2</sub>S) and the enzymatic characteristics are described accordingly. Cystathionine &#946;-synthase (CBS) and cystathionine &#947;-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H<sub>2</sub>S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H<sub>2</sub>S levels, see Szabo and Papapetropoulos, 2017 [<a href="">4</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Pattern recognition receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Clare Bryant Tom P. Monie Pattern Recognition Receptors (PRRs, [<a href="">83</a>]) (<b>nomenclature as agreed by <u>NC-IUPHAR</u> sub-committee on Pattern Recognition Receptors,</b> [<a href="">15</a>]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1&#946; cleavage and secretion, and others in the initiation of the type I interferon response. <br><br>PRRs included in the Guide To PHARMACOLOGY are:<br><br><b>Catalytic PRRs</b> (see links below this overview)<br>Toll-like receptors (TLRs)<br>Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)<br>RIG-I-like receptors (RLRs)<br><a href="ObjectDisplayForward?objectId=1620">Caspase 4</a> and <a href="ObjectDisplayForward?objectId=1621">caspase 5</a> <br><br><b>Non-catalytic PRRs</b><br><a href="FamilyDisplayForward?familyId=942">Absent in melanoma (AIM)-like receptors</a> (ALRs)<br><a href="FamilyDisplayForward?familyId=945">C-type lectin-like receptors (CLRs)</a><br><a href="FamilyDisplayForward?familyId=929">Other pattern recognition receptors</a><br><a href="ObjectDisplayForward?objectId=2843">Advanced glycosylation end-product specific receptor</a> (RAGE)<br> 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Tumour necrosis factor (TNF) receptor family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 David MacEwan Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy [<a href="">4</a>, <a href="">5</a>, <a href="">38</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## SLC51 family of steroid-derived molecule transporters (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Paul A. Dawson The SLC51 organic solute transporter family of transporters is a pair of heterodimeric proteins which regulate bile salt movements in the small intestine, bile duct, and liver, as part of the enterohepatic circulation [<a href="">1</a>, <a href="">3</a>]. OST&#945;/OST&#946; is also expressed in steroidogenic cells of the brain and adrenal gland, where it may contribute to steroid movement [<a href="">4</a>]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [<a href="">3</a>, <a href="">1</a>]. OST&#945;/OST&#946; heterodimers have been shown to transport <a href= "">[<sup>3</sup>H]taurocholic acid</a>, <a href= "">[<sup>3</sup>H]dehydroepiandrosterone sulphate</a>, <a href= "">[<sup>3</sup>H]estrone-3-sulphate</a>, <a href= "">[<sup>3</sup>H]pregnenolone sulphate</a> and <a href= "">[<sup>3</sup>H]dehydroepiandrosterone sulphate</a> [<a href="">1</a>, <a href="">3</a>, <a href="">4</a>]. OST&#945;/OST&#946;-mediated transport of bile salts is inhibited by <a href= "">clofazimine</a> [<a href="">7</a>]. OST&#945; is suggested to be a seven TM protein, while OST&#946; is a single TM 'ancillary' protein, both of which are thought to have intracellular C-termini [<a href="">5</a>]. Both proteins function in solute transport and bimolecular fluorescence complementation studies suggest the possibility of OST&#945; homo-oligomers, as well as OST&#945;/OST&#946; hetero-oligomers [<a href="">5</a>, <a href="">2</a>]. An inherited mutation in OST&#946; is associated with congenital diarrhea in children [<a href="">6</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Chemerin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Anthony P. Davenport Amy E. Monaghan Nomenclature for the chemerin receptors is presented as <b> recommended by <u>NC-IUPHAR</u> [<a href="">14</a>, <a href="">41</a>]</b>). The chemoattractant protein and adipokine, <a href= "">chemerin</a>, has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin<sub>1</sub> was the founding family member, and when <i>GPR1</i> was de-orphanised it was re-named Chermerin<sub>2</sub> [<a href="">41</a>]. Chemerin<sub>1</sub> is also activated by the lipid-derived, anti-inflammatory ligand <a href= "">resolvin E1</a> (RvE1), which is formed <i>via</i> the sequential metabolism of <a href= "">EPA</a> by aspirin-modified cyclooxygenase and lipoxygenase [<a href="">2</a>, <a href="">3</a>]. In addition, two GPCRs for <a href= "">resolvin D1</a> (RvD1) have been identified: FPR2/ALX, the lipoxin A<sub>4</sub> receptor, and GPR32, an orphan receptor [<a href="">43</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Succinate receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Anthony P. Davenport Julien Hanson Wen Chiy Liew <b>Nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">7</a>]</b>. The Succinate receptor has been identified as being activated by physiological levels of the Kreb's cycle intermediate succinate and other dicarboxylic acids such as maleate in 2004. Since its pairing with its endogenous ligand, the receptor has been the focus of intensive research and its role has been evidenced in various (patho)physiological processes such as regulation of renin production, retinal angiogenesis, inflammation or immune response. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Oxoglutarate receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Anthony P. Davenport Wen Chiy Liew <b>Nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">2</a>]</b>. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Integrins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Richard W. Farndale Gavin E. Jarvis Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the 'Catalytic receptors' section of the database until more stringent criteria from NC-IUPHAR allows precise definition of their classification.<br><br>Integrins are heterodimeric entities, composed of &#945; and &#946; subunits, each 1TM proteins, which bind components of the extracellular matrix or counter-receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its &#945; subunit, and if present (in &#945;1, &#945;2, &#945;10, &#945;11, &#945;D, &#945;E, &#945;L, &#945;M and &#945;X), this I domain contains the ligand binding site. All &#946; subunits possess a similar I-like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an &#945; subunit I domain precludes ligand binding through the &#946; subunit. Integrins provide a link between ligand and the actin cytoskeleton (through typically short intracellular domains). Integrins bind several divalent cations, including a Mg<sup>2+</sup> ion in the I or I-like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin-linked kinase. Cellular activation regulates integrin ligand affinity <i>via</i> inside-out signalling and ligand binding to integrins can regulate cellular activity <i>via</i> outside-in signalling.<br><br>Several drugs that target integrins are in clinical use including: (1) <a href= "">abciximab</a> (&#945;IIb&#946;3) for short term prevention of coronary thrombosis, (2) <a href= "">vedolizumab</a> (&#945;4&#946;7) to reduce gastrointestinal inflammation, and (3) <a href= "">natalizumab</a> (&#945;4&#946;1) in some cases of severe multiple sclerosis. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Ceramide turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Anthony H. Futerman Ceramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates <a href= "">3-ketosphinganine</a>, which is reduced to <a href= "">sphinganine</a> (dihydrosphingosine). N-Acylation allows the formation of dihydroceramides, which are subsequently reduced to form ceramides. Once synthesized, ceramides are trafficked from the ER to the Golgi bound to the ceramide transfer protein, CERT (<a href="!/hgnc_id/HGNC:2205"><i>COL4A3BP</i></a>, <a href="">Q9Y5P4</a>). Ceramide can be metabolized via multiple routes, ensuring tight regulation of its cellular levels. Addition of phosphocholine generates sphingomyelin while carbohydrate is added to form glucosyl- or galactosylceramides. Ceramidase re-forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Sphingosine 1-phosphate turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Nigel J Pyne Susan Pyne S1P (<a href= "">sphingosine 1-phosphate</a>) is a bioactive lipid which, after release from cells via certain transporters, acts as a ligand for a family of five S1P-specific G protein-coupled receptors (S1P1-5). However, it also has a number of intracellular targets. S1P is formed by the ATP-dependent phosphorylation of sphingosine, catalysed by two isoforms of sphingosine kinase (EC It can be dephosphorylated back to sphingosine by sphingosine 1-phosphate phosphatase (EC 3.1.3) or cleaved into phosphoethanolamine and hexadecenal by sphingosine 1-phosphate lyase (EC Recessive mutations in the S1P lyase (SPL) gene underlie a recently identified sphingolipidosis: SPL Insufficiency Syndrome (SPLIS). In general, S1P promotes cell survival, proliferation, migration, adhesion and inhibition of apoptosis. Intracellular S1P affects epigenetic regulation, endosomal processing, mitochondrial function and cell proliferation/senescence. S1P has myriad physiological functions, including vascular development, lymphocyte trafficking and neurogenesis. However, S1P is also involved in a number of diseases such as cancer, inflammation and fibrosis. Therefore, its GPCRs and enzymes of synthesis and degradation are a major focus for drug discovery. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Hydrolases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Stephen P.H. Alexander Patrick Doherty David Fairlie Christopher J. Fowler Christopher M. Overall Neil Rawlings Christopher Southan Anthony J. Turner Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 <a href="" target="_blank">(P23141</a>), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Regulators of G protein Signaling (RGS) proteins (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Mohammed Alqinyah Christopher Bodle Josephine Bou Dagher Bandana Chakravarti Shreoshi P. Choudhuri Kirk M. Druey Rory A. Fisher Kyle J. Gerber John R. Hepler Shelley B. Hooks Havish S. Kantheti Behirda Karaj Jae-Kyung Lee Zili Luo Kirill Martemyanov Luke D. Mascarenhas Hoa Phan Thi Nhu David L. Roman Vincent Shaw Benita Sjögren Katherine E. Squires Laurie Sutton Thomas M. Wilkie Keqiang Xie Yalda Zolghadri Regulators of G protein signalling (RGS) proteins display a common RGS domain that interacts with the GTP-bound G&#945; subunits of heterotrimeric G proteins, enhancing GTP hydrolysis by stabilising the transition state [<a href="">29</a>, <a href="">419</a>, <a href="">418</a>], leading to a termination of GPCR signalling. Interactions through protein:protein interactions of many RGS proteins have been identified for targets other than heteromeric G proteins. Sequence analysis of the 20 RGS proteins suggests four families of RGS: RZ, R4, R7 and R12 families. Many of these proteins have been identified to have effects other than through targetting G proteins. Included here is RGS4 for which a number of pharmacological inhibitors have been described. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Small monomeric GTPases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Elena Faccenda Small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Notch receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Thiruma V. Arumugam Christopher Sobey The canonical Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [<a href="">2</a>]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by &#947;-secretase is required for downstream signalling and Notch-induced transcriptional modulation [<a href="">15</a>, <a href="">3</a>, <a href="">11</a>, <a href="">22</a>]. This is why &#947;-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is <a href= "">RO4929097</a> [<a href="">8</a>], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [<a href="">19</a>].<br><br>Aberrant Notch signalling is implicated in a number of human cancers [<a href="">12</a>, <a href="">20</a>, <a href="">6</a>, <a href="">16</a>], with <a href= "">demcizumab</a> and <a href= "">tarextumab</a> identified as antibody inhibitors of ligand:receptor binding [<a href="">13</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## S33: Prolyl aminopeptidase (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Stephen P.H. Alexander Patrick Doherty Christopher J. Fowler Peptidase family S33 contains mainly exopeptidases that act at the N-terminus of peptides. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Endocannabinoid turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Stephen P.H. Alexander Patrick Doherty Christopher J. Fowler Jürg Gertsch Mario van der Stelt The principle endocannabinoids are 2-acylglycerol esters, such as <a href= "">2-arachidonoylglycerol</a> (2-AG), and <i>N</i>-acylethanolamines, such as <a href= "">anandamide</a> (<i>N</i>-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [<a href="">19</a>]. <a href="/FamilyDisplayForward?familyId=783#2535">FABP5</a> (<a href="" target="_blank">Q01469</a>) has been suggested to act as a canonical intracellular endocannabinoid transporter <i>in vivo</i> [<a href="">12</a>]. For the generation of <a href= "">2-arachidonoylglycerol</a>, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for <a href= "">anandamide</a> synthesis have been described, the best characterized of which involves <i>N</i>-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [<a href="">49</a>]). A transacylation enzyme which forms <i>N</i>-acylphosphatidylethanolamines has recently been identified as a cytosolic enzyme, <a href="!/hgnc_id/HGNC:24791"><i>PLA2G4E</i></a> (<a href=" ">Q3MJ16</a>) [<a href="">43</a>]. <i> In vitro</i> experiments indicate that the endocannabinoids are also substrates for oxidative metabolism <i>via</i> cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [<a href="">4</a>, <a href="">16</a>, <a href="">51</a>]. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## NADPH oxidases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Albert van der Vliet The two DUOX enzymes were originally identified as participating in the production of hydrogen peroxide as a pre-requisite for thyroid hormone biosynthesis in the thyroid gland [<a href="">6</a>].<br>NOX enzymes function to catalyse the reduction of molecular oxygen to superoxide and various other reactive oxygen species (ROS). They are subunits of the NADPH oxidase complex. 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement## Receptor guanylyl cyclase (RGC) family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database 2019-09-17T16:06:40+01:00 Annie Beuve Peter Brouckaert John C. Burnett, Jr. Andreas Friebe John Garthwaite Adrian J. Hobbs Doris Koesling Michaela Kuhn Lincoln R. Potter Michael Russwurm Harald H.H.W. Schmidt Johannes-Peter Stasch Scott A. Waldman The mammalian genome encodes transmembrane and soluble receptor guanylyl cyclases, both of which have enzyme activities which convert <a href= "">guanosine-5'-triphosphate</a> to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (<a href= "">cyclic GMP</a>). 2019-09-16T00:00:00+01:00 ##submission.copyrightStatement##