IUPHAR/BPS Guide to Pharmacology CITE 2021-09-29T10:27:02+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> Acetylcholine receptors (muscarinic) in GtoPdb v.2021.3 2021-09-29T10:27:02+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 David Thal Andrew B. Tobin Celine Valant Jurgen Wess <p>Muscarinic acetylcholine receptors (mAChRs) (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Muscarinic Acetylcholine Receptors [<a href="">50</a>]</b>) are activated by the endogenous agonist <a href="">acetylcholine</a>. All five (M1<sub></sub>-M5<sub></sub>) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M<sub>1</sub>, M<sub>3</sub>, and M<sub>5</sub> mAChRs preferentially couple to G<sub>q/11</sub> proteins, whilst M<sub>2</sub> and M<sub>4</sub> mAChRs predominantly couple to G<sub>i/o</sub> proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including <a href="">pilocarpine</a> for the treatment of elevated intra-ocular pressure and glaucoma, and <a href="">atropine</a> for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Adrenoceptors in GtoPdb v.2021.3 2021-09-29T10:27:01+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 <span><b>The nomenclature of the Adrenoceptors has been agreed by the <u>NC-IUPHAR</u> Subcommittee on Adrenoceptors [<a href="">60</a>, <a href="">186</a>]</b>.<br><br> <b>Adrenoceptors, &#945;<sub>1</sub></b><br> The three &#945;<sub>1</sub>-adrenoceptor subtypes &#945;<sub>1A</sub>, &#945;<sub>1B</sub> and &#945;<sub>1D</sub> 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="">doxazosin</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 FLprazosin- QAPB) are used to examine cellular localisation of &#945;<sub>1</sub>-adrenoceptors. &#945;<sub>1</sub>-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (<a href="">alfuzosin</a>, <a href="">doxazosin</a>, <a href="">terazosin</a>, <a href="">tamsulosin</a> and <a href="">silodosin</a>, with the last two compounds being &#945;1<sub>A</sub>-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (<a href="">doxazosin</a>, <a href="">terazosin</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. <br> <br><b>Adrenoceptors, &#945;<sub>2</sub> </b> <br>The three &#945;<sub>2</sub>-adrenoceptor subtypes &#945;<sub>2A</sub>, &#945;<sub>2B</sub> and &#945;<sub>2C</sub> 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 are species variations 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 (relatively little used) and counteracts opioid withdrawal. <a href="">dexmedetomidine</a> (also <a href="">xylazine</a>) is increasingly used as a sedative and analgesic in human [<a href="">31</a>] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;<sub>2</sub>-adrenoceptor antagonist <a href="">mirtazapine</a> is used 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. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. <br><br><b>Adrenoceptors, &#946; </b><br>The three &#946;-adrenoceptor subtypes &#946;<sub>1</sub>, &#946;<sub>2</sub> and &#946;<sub>3</sub> 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 selective antagonists for &#946;<sub>1</sub>- and &#946;<sub>2</sub>- relative to &#946;<sub>3</sub>-adrenoceptors. <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> (low potency) 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 between the three &#946;- subtypes [<a href="">320</a>] whereas <a href="">L-748337</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. 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 cardiac arrhythmias (<a href="">atenolol</a>, <a href="">bisoprolol</a>, <a href="">esmolol</a>) and cardiac failure (<a href="">metoprolol</a>, <a href="">nebivolol</a>) but also in combination with other treatments to treat hypertension (<a href="">atenolol</a>, <a href="">betaxolol</a>, <a href="">bisoprolol</a>, <a href="">metoprolol</a> and <a href="">nebivolol</a>) [<a href="">507</a>]. 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. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [<a href="">189</a>].</span> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Complement peptide receptors in GtoPdb v.2021.3 2021-09-29T10:27:01+01:00 Antonia Cianciulli Liam Coulthard Owen Hawksworth John D. Lee Xaria X. Li Vincenzo Mitolo Peter Monk Maria A. Panaro Trent M. Woodruff <p>Complement peptide receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Complement peptide receptors [<a href="">107</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, C5aR1 and C5aR2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Bradykinin receptors in GtoPdb v.2021.3 2021-09-29T10:27:00+01:00 Joseph Coulson Réjean Couture Alexander Faussner Fernand Gobeil Jr Fredrik Leeb-Lundberg Francois Marceau Werner Muller-Esterl Doug Pettibone Bruce Zuraw <p>Bradykinin (or kinin) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on Bradykinin (kinin) Receptors [<a href="">91</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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Calcium-sensing receptor in GtoPdb v.2021.3 2021-09-29T10:27:00+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 <p>The calcium-sensing receptor (CaS, <b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">47</a>] and subsequently updated [<a href="">77</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="">78</a>]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [<a href="">14</a>, <a href="">110</a>], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [<a href="">36</a>, <a href="">47</a>, <a href="">61</a>, <a href="">108</a>, <a href="">109</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="">148</a>, <a href="">54</a>]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [<a href="">18</a>] or decreased extracellular ionic strength [<a href="">109</a>]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Class A Orphans in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Stephen P.H. Alexander Jim Battey Helen E. Benson Richard V. Benya Tom I. Bonner Anthony P. Davenport Khuraijam Dhanachandra Singh 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 <div><p>Table 1 lists a number of putative GPCRs identified by <b> <u>NC-IUPHAR</u> [<a href="">161</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="">121</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> </p><table class="tableizer-table"> <tr><td><a href=""><i>GPR3</i></a></td><td><a href=""><i>GPR4</i></a></td><td><a href=""><i>GPR6</i></a></td><td><a href=""><i>GPR12</i></a></td><td><a href=""><i>GPR15</i></a></td><td><a href=""><i>GPR17</i></a></td><td><a href=""><i>GPR20</i></a></td></tr> <tr><td><a href=""><i>GPR22</i></a></td><td><a href=""><i>GPR26</i></a></td><td><a href=""><i>GPR31</i></a></td><td><a href=""><i>GPR34</i></a></td><td><a href=""><i>GPR35</i></a></td><td><a href=""><i>GPR37</i></a></td><td><a href=""><i>GPR39</i></a></td></tr> <tr><td><a href=""><i>GPR50</i></a></td><td><a href=""><i>GPR63</i></a></td><td><a href=""><i>GRP65</i></a></td><td><a href=""><i>GPR68</i></a></td><td><a href=""><i>GPR75</i></a></td><td><a href=""><i>GPR84</i></a></td><td><a href=""><i>GPR87</i></a></td></tr> <tr><td><a href=""><i>GPR88</i></a></td><td><a href=""><i>GPR132</i></a></td><td><a href=""><i>GPR149</i></a></td><td><a href=""><i>GPR161</i></a></td><td><a href=""><i>GPR183</i></a></td><td><a href=""><i>LGR4</i></a></td><td><a href=""><i>LGR5</i></a></td></tr> <tr><td><a href=""><i>LGR6</i></a></td><td><a href=""><i>MAS1</i></a></td><td><a href=""><i>MRGPRD</i></a></td><td><a href=""><i>MRGPRX1</i></a></td><td><a href=""><i>MRGPRX2</i></a></td><td><a href=""><i>P2RY10</i></a></td><td><a href=""><i>TAAR2</i></a></td></tr> </table> <br>In addition the orphan receptors <a href=""><i>GPR18</i></a>, <a href=""><i>GPR55</i></a> and <a href=""><i>GPR119</i></a> which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (<a href="">GPR18, GPR55 and GPR119</a>).</div> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Adhesion Class GPCRs in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>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="">9</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="">101</a>, <a href="">403</a>]. Several receptors have been suggested to function as mechanosensors [<a href="">309</a>, <a href="">280</a>, <a href="">383</a>, <a href="">35</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="">122</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## G protein-coupled estrogen receptor in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Edward J. Filardo Richard Neubig Eric R. Prossnitz <p>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="">25</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="">6</a>]. There are observations of both cell-surface and intracellular expression of the GPER receptor [<a href="">28</a>, <a href="">33</a>]. Selective agonist/ antagonists for GPER have been characterized [<a href="">25</a>]. Antagonists of the nuclear estrogen receptor, such as <a href="">fulvestrant</a> [<a href="">11</a>], <a href="">tamoxifen</a> [<a href="">28</a>, <a href="">33</a>] and <a href="">raloxifene</a> [<a href="">24</a>], as well as the flavonoid 'phytoestrogens' <a href="">genistein</a> and <a href="">quercetin</a> [<a href="">17</a>], are agonists of GPER. A complete review of GPER pharmacology has been published [<a href="">25</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="">25</a>, <a href="">26</a>, <a href="">19</a>, <a href="">16</a>, <a href="">9</a>]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer (<a href="" target="_blank">NCT04130516</a>).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Class Frizzled GPCRs in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Elisa Arthofer Jacomijn Dijksterhuis Belma Hot Paweł Kozielewicz Matthias Lauth Jessica Olofsson Julian Petersen Tilman Polonio Gunnar Schulte Katerina Strakova Jana Valnohova Shane Wright <p>Receptors of the Class Frizzled (FZD, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> subcommittee on the Class Frizzled GPCRs [<a href="">175</a>]</b>), are GPCRs originally identified in <i>Drosophila</i> [<a href="">19</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="">175</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. WNT/&#946;-catenin-independent signalling can also be activated by FZD subtype-specific WNT surrogates [<a href="">133</a>]. &#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="">33</a>, <a href="">178</a>, <a href="">150</a>], the elevation of intracellular calcium [<a href="">184</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="">56</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="">239</a>, <a href="">240</a>, <a href="">102</a>, <a href="">174</a>]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [<a href="">240</a>]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [<a href="">22</a>], as well as for &#946;-catenin-dependent [<a href="">13</a>] and -independent [<a href="">89</a>, <a href="">14</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="">Ryk</a>, <a href="">ROR1</a>, <a href="">ROR2</a> and Kremen, which may also function as independent signalling proteins.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Galanin receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Andrew L. Gundlach Philip J. Ryan <p>Galanin receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">57</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="">52</a>]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1-14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (<i>e.g</i>. human galanin-1-19 [<a href="">21</a>] and porcine galanin-5-29 [<a href="">170</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="">170</a>]) have been reported. More recently, the newly-identified peptide, spexin (SPX), has been reported to activate human GAL2 and GAL3 (but not GAL1) receptors in heterologous expression systems; and to alter GAL2/3 receptor-related behaviours in animals [<a href="">89</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Ghrelin receptor in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Anthony P. Davenport Birgitte Holst Matthias Kleinz Janet J. Maguire Bjørn B. Sivertsen <p>The ghrelin receptor (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee for the Ghrelin receptor [<a href="">19</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="">74</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="">49</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="">133</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="">58</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="">44</a>]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [<a href="">35</a>, <a href="">68</a>] inhibits ghrelin receptor-induced GH secretion and food intake [<a href="">35</a>]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [<a href="">71</a>]. In cell systems, the ghrelin receptor is constitutively active [<a href="">45</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="">93</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Glucagon receptor family in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>The glucagon family of receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on the Glucagon receptor family [<a href="">162</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="">119</a>]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the associated signaling events see de Graaf <i>et al</i>., 2016 [<a href="">89</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Gonadotrophin-releasing hormone receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Laura H. Heitman Adriaan P. IJzerman Craig A. McArdle Adam J Pawson <p>GnRH<sub>1</sub> and GnRH<sub>2</sub> receptors (<b>provisonal nomenclature [<a href="">39</a>]</b>, also called Type I and Type II GnRH receptor, respectively [<a href="">85</a>]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [<a href="">85</a>, <a href="">84</a>, <a href="">114</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="">85</a>, <a href="">84</a>, <a href="">114</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="">85</a>, <a href="">84</a>, <a href="">114</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="">58</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="">58</a>]. GnRH<sub>1</sub> 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. GnRH<sub>2</sub> receptors are expressed by some primates but not by humans [<a href="">88</a>]. Phylogenetic classifications divide GnRH receptors into three [<a href="">85</a>] or five groups [<a href="">129</a>] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH<sub>1</sub> receptor in complex with <a href="">elagolix</a> has been elucidated [<a href="">132</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Histamine receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>Histamine receptors (<b>nomenclature as agreed by the <u> NC-IUPHAR</u> Subcommittee on Histamine Receptors [<a href="">80</a>, <a href="">173</a>]</b>) are activated by the endogenous ligand <a href="">histamine</a>. Marked species differences exist between histamine receptor orthologues [<a href="">80</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> &gt; H<sub>2</sub> &gt; H<sub>1</sub> [<a href="">173</a>]. Some agonists at the human H<sub>3</sub> receptor display significant ligand bias [<a href="">182</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="">adriforant</a>; Phase IIa) [<a href="">173</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="">216</a>, <a href="">8</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Lysophospholipid (LPA) receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+01:00 Victoria Blaho Jerold Chun Danielle Jones Deepa Jonnalagadda Yasuyuki Kihara Tony Ngo Manisha Ray Valerie P. Tan <p>Lysophosphatidic acid (LPA) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Lysophospholipid Receptors [<a href="">55</a>, <a href="">19</a>, <a href="">82</a>, <a href="">129</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="">40</a>], This discovery represented the beginning of the de-orphanisation of members of the endothelial differentiation gene (edg) family, as other LPA and sphingosine 1-phosphate (S1P) receptors were found. Five additional LPA receptors (LPA<sub>2,3,4,5,6</sub>) have since been identified [<a href="">82</a>] and their gene nomenclature codified for human <i>LPAR1, LPAR2, etc</i>. (HUGO Gene Nomenclature Committee, HGNC) and <i>Lpar1, Lpar2, etc</i>. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function of their corresponding proteins. The crystal structure of LPA1 is solved and indicates that LPA accesses the extracellular binding pocket, consistent with its proposed delivery via autotaxin [<a href="">13</a>]. These studies have also implicated cross-talk with endocannabinoids <i>via</i> phosphorylated intermediates that can also activate these receptors. The binding affinities to LPA<sub>1</sub> of unlabeled, natural LPA and anandamide phosphate (AEAp) were measured using backscattering interferometry (pK<sub>d</sub> = 9) [<a href="">83</a>, <a href="">104</a>]. Utilization of this method indicated affinities that were 77-fold lower than when measured using radioactivity-based protocols [<a href="">128</a>]. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Multiple groups have independently published validation of all six LPA receptors described in these tables, and further validation was achieved using a distinct read-out via a novel TGF&#945; "shedding* assay [<a href="">48</a>]. <a href="">LPA</a> has been proposed to be a ligand for GPR35 [<a href="">94</a>], supported by a study revealing that LPA modulates macrophage function through GPR35 [<a href="">54</a>]. However chemokine (C-X-C motif) ligand 17 (<a href="">CXCL17</a>) is reported to be a ligand for GPR35/CXCR8 [<a href="">76</a>]. Moreover, LPA has also been described as an agonist for the transient receptor potential (Trp) ion channels TRPV1 [<a href="">87</a>] and TRPA1 [<a href="">58</a>]. All of these proposed non-GPCR receptor identities require confirmation and are not currently recognized as <i>bona fide</i> LPA receptors.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Melanocortin receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>Melanocortin receptors (<b>provisional nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">41</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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Melatonin receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>Melatonin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR </u>Subcommittee on Melatonin Receptors [<a href="">40</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>.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Metabotropic glutamate receptors in GtoPdb v.2021.3 2021-09-29T10:26:59+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 <p>Metabotropic glutamate (mGlu) receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Metabotropic Glutamate Receptors [347]</b>) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [<a href="">138</a>]. The mGlu family is composed of eight members (named mGlu1<sub></sub> to mGlu<sub>8</sub>) 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 <i>via</i> a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. 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="">198</a>, <a href="">271</a>, <a href="">264</a>, <a href="">399</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="">87</a>, <a href="">429</a>, <a href="">61</a>]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor dimers [<a href="">189</a>]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [<a href="">88</a>]. First well characterized in transfected cells, co-localization and specific pharmacological properties also suggest the existence of such heterodimers in the brain [<a href="">266</a>].[<a href="">436</a>, <a href="">143</a>, <a href="">279</a>]. Beyond heteromerization with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [<a href="">138</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="">30</a>] and antagonized by <a href="">(S)-hexylhomoibotenic acid</a> [<a href="">232</a>]. Group-II mGlu receptors may be activated by <a href="">LY389795</a> [<a href="">265</a>], <a href="">LY379268</a> [<a href="">265</a>], <a href="">eglumegad</a> [<a href="">350</a>, <a href="">430</a>], <a href="">DCG-IV</a> and <a href="">(2<i>R</i>,3<i>R</i>)-APDC</a> [<a href="">351</a>], and antagonised by <a href="">eGlu</a> [<a href="">168</a>] and <a href="">LY307452</a> [<a href="">421</a>, <a href="">103</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="">128</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="">183</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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Neuropeptide S receptor in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Girolamo Caló Olivier Civelli Rainer K. Reinscheid Chiara Ruzza <p>The neuropeptide S receptor (NPS, <b>provisional nomenclature [<a href="">23</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>).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Opioid receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+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 <p>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="">121</a>, <a href="">100</a>, <a href="">91</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="">294</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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Orexin receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Paul Coleman Luis de Lecea Anthony Gotter Jim Hagan Daniel Hoyer Thomas Kilduff Jyrki P. Kukkonen Rod Porter John Renger Jerome M Siegel Gregor Sutcliffe Neil Upton Christopher J. Winrow <p>Orexin receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Orexin receptors [<a href="">42</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="">109</a>]. Currently the only orexin receptor ligands in clinical use are <a href="">suvorexant</a> and <a href="">lemborexant</a>, which are used as hypnotics. Orexin receptor crystal structures have been solved [<a href="">134</a>, <a href="">133</a>, <a href="">54</a>, <a href="">117</a>, <a href="">46</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## P2Y receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+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 <p>P2Y receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on P2Y Receptors [<a href="">3</a>, <a href="">5</a>, <a href="">192</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 [47, <a href="">110</a>, <a href="">190</a>, <a href="">383</a>, <a href="">396</a>]. 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="">241</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="">53</a>, <a href="">323</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Parathyroid hormone receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+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 <p>The parathyroid hormone receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Parathyroid Hormone Receptors [<a href="">49</a>]</b>) are class 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. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1-13) and PTHrP-(14-36)) bound to the PTH1 receptor-G<sub>s</sub> complex has been resolved by cryo-electron microscopy [<a href="">147</a>]. Another structure of a PTH-(1-34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [<a href="">34</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Prolactin-releasing peptide receptor in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Vanni Caruso Rebecca Hills Malin Lagerstrom Tatsushi Onaka Helgi Schiöth <p>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 (43RFa)</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="">31</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).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Proteinase-activated receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Nigel Bunnett Kathryn DeFea Justin Hamilton Morley D. Hollenberg Rithwik Ramachandran JoAnn Trejo <p>Proteinase-activated receptors (PARs, <b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Proteinase-activated Receptors [<a href="">39</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="">82</a>]. PAR2 activation by NE regulates inflammation and pain responses [<a href="">111</a>, <a href="">72</a>] and triggers mucin secretion from airway epithelial cells [<a href="">112</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Relaxin family peptide receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Ross Bathgate Thomas Dschietzig Andrew L. Gundlach Michelle Halls Roger Summers <p>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="">81</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="">184</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="">183</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="">189</a>] and RXFP2 [<a href="">91</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="">186</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="">225</a>, <a href="">104</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Urotensin receptor in GtoPdb v.2021.3 2021-09-29T10:26:58+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 <p>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="">93</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="">92</a>]. Several structural forms of U-II exist in fish and amphibians [<a href="">93</a>]. 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="">2</a>, <a href="">20</a>, <a href="">63</a>, <a href="">69</a>, <a href="">72</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="">61</a>, <a href="">53</a>, <a href="">10</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="">86</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="">93</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## 5-HT<sub>3</sub> receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Nicholas M. Barnes Tim G. Hales Sarah C. R. Lummis Beate Niesler John A. Peters <p>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="">69</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 4 transmembrane (TM) subunits that form an intrinsic cation selective channel [<a href="">7</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="">86</a>, <a href="">125</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="">127</a>, <a href="">66</a>, <a href="">161</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="">161</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="">85</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="">9</a>], but this is inconsistent with recent reports which show at least one A-A interface [<a href="">99</a>, <a href="">154</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="">35</a>, <a href="">44</a>, <a href="">59</a>, <a href="">88</a>, <a href="">143</a>, <a href="">132</a>, <a href="">82</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="">19</a>], but see [<a href="">44</a>, <a href="">33</a>, <a href="">38</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="">99</a>, <a href="">154</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="">142</a>, <a href="">139</a>, <a href="">73</a>]. The potential diversity of 5-HT<sub>3</sub> receptors is increased by alternative splicing of the genes <i>HTR3A</i> and <i>HTR3E</i> [<a href="">67</a>, <a href="">21</a>, <a href="">127</a>, <a href="">126</a>, <a href="">123</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="">156</a>, <a href="">82</a>, <a href="">123</a>]. To date, inclusion of the 5-HT<sub>3</sub>A subunit appears imperative for 5-HT<sub>3</sub> receptor function.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Calcium- and sodium-activated potassium channels (K<sub>Ca</sub>, K<sub>Na</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Richard Aldrich K. George Chandy Stephan Grissmer George A. Gutman GAGutman@UCI.Edu Leonard K. Kaczmarek Aguan D. Wei Heike Wulff <p>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="">125</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).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Elvir Becirovic Martin Biel Stefanie Fenske Verena Hammelmann Franz Hofmann U. Benjamin Kaupp <span><b>Cyclic nucleotide-gated (CNG) channels</b> are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems. 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="">83</a>, <a href="">120</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="">181</a>] and the pineal gland [<a href="">71</a>]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include hyperolarisation-activated, cyclic nucleotide-gated channels (HCN), ether-a-go-go and certain plant potassium channels.<br><br>The <b>HCN channels</b> 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 bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves 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="">64</a>, <a href="">192</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="">139</a>, <a href="">146</a>, <a href="">140</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="">108</a>].</b></span> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## GABA<sub>A</sub> receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Delia Belelli Tim G. Hales Jeremy J. Lambert Bernhard Luscher Richard Olsen John A. Peters Uwe Rudolph Werner Sieghart <p>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 'GABA<sub>A</sub>, slow' [<a href="">45</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="">278</a>, <a href="">235</a>, <a href="">236</a>, <a href="">283</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="">71</a>]. The three &#961;-subunits, (&#961;1-3) function as either homo- or hetero-oligomeric assemblies [<a href="">359</a>, <a href="">50</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="">359</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="">16</a>, <a href="">235</a>, <a href="">236</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="">168</a>, <a href="">235</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="">209</a>, <a href="">272</a>, <a href="">83</a>, <a href="">19</a>, <a href="">288</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="">254</a>]; reviewed by [<a href="">282</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="">356</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="">52</a>, <a href="">140</a>, <a href="">188</a>, <a href="">316</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 &#948; subunit appear to be exclusively extrasynaptic. <br><br><b><u>NC-IUPHAR</u> [<a href="">16</a>, <a href="">235</a>, <a href="">3</a>, <a href="">2</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="">235</a>, <a href="">236</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="">16</a>, <a href="">95</a>, <a href="">168</a>, <a href="">173</a>, <a href="">143</a>, <a href="">278</a>, <a href="">216</a>, <a href="">235</a>, <a href="">236</a>] and [<a href="">9</a>, <a href="">10</a>]. Agents that discriminate between &#945;-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example <i>via</i> &#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="">359</a>, <a href="">50</a>, <a href="">145</a>, <a href="">223</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 <a href="">alprazolam</a> and <a href="">diazepam</a> [<a href="">198</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Glycine receptors in GtoPdb v.2021.3 2021-09-29T10:26:58+01:00 Joseph. W. Lynch Lucia G. Sivilotti Trevor G. Smart <p>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 and Zn<sup>2+</sup>- activated channels. 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="">33</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="">83</a>, <a href="">93</a>, <a href="">21</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 adult form of the receptor contains &#945;1 (or &#945;3) and &#946; subunits whereas the immature form is mostly composed of only &#945;2 subunits. The &amp;a;pha;4 subunit is a pseudogene in humans. High resolution molecular structures are available for the &#945;1 and &#945;3 homomeric receptors [<a href="">50</a>, <a href="">20</a>]. As in other Cys-loop receptors, the orthosteric binding site for agonists and the competitive antagonist <a href="">strychnine</a> is formed at the interfaces between the subunits&#8217; extracellular domains. 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, <i>via</i> an amphipathic sequence within the large intracellular loop region, to gephyrin. This 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="">56</a>, <a href="">54</a>, <a href="">88</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="">124</a>, <a href="">123</a>]. Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [<a href="">96</a>]. Intracellular <a href="">Ca<sup>2+</sup></a> appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [<a href="">27</a>]. Extracellular <a href="">Zn<sup>2+</sup></a> potentiates GlyR function at nanomolar concentrations [<a href="">86</a>]. and causes inhibition at higher micromolar concentrations (17).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Inwardly rectifying potassium channels (K<sub>IR</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:58+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 <p>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).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Ionotropic glutamate receptors in GtoPdb v.2021.3 2021-09-29T10:26:57+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 <p>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="">35</a>, <a href="">92</a>, <a href="">155</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), 3 TM domains (M1, M3 and M4), a channel lining re-entrant 'p-loop' (M2) located between M1 and M3 and an intracellular carboxy- terminal domain (CTD) [<a href="">99</a>, <a href="">68</a>, <a href="">107</a>, <a href="">155</a>, <a href="">82</a>]. The X-ray structure of a homomeric ionotropic glutamate receptor (GluA2- see below) has recently been solved at 3.6&#197; resolution [<a href="">143</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="">71</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="">35</a>, 66, <a href="">31</a>, <a href="">77</a>, <a href="">42</a>, <a href="">114</a>, <a href="">24</a>, <a href="">65</a>, <a href="">155</a>, <a href="">112</a>, <a href="">113</a>, <a href="">162</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="">28</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="">41</a>, <a href="">25</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="">48</a>, <a href="">99</a>, <a href="">71</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="">43</a>, <a href="">103</a>, <a href="">153</a>, <a href="">64</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="">87</a>, <a href="">119</a>, <a href="">118</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="">119</a>, <a href="">65</a>, <a href="">118</a>]). Kainate receptors may also exhibit 'metabotropic' functions [<a href="">87</a>, <a href="">131</a>]. As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits (Neto proteins, [<a href="">118</a>, <a href="">88</a>]). An important function difference between AMPA and kainate receptors is that the latter require extracellular Na<sup>+</sup> and Cl<sup>-</sup> for their activation [<a href="">11</a>, <a href="">120</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 <a href="">argiotoxin</a> and <a href="">joro spider toxin</a>s and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 [<a href="">139</a>, <a href="">63</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="">87</a>, <a href="">118</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="">30</a>, <a href="">63</a>, <a href="">91</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 <a href="">cyclothiazide</a> 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="">103</a>]. Splice variants of GluK1-3 also exist which affects their trafficking [<a href="">87</a>, <a href="">118</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Nicotinic acetylcholine receptors (nACh) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Cecilia Gotti Michael. J. Marks Michael.Marks@Colorado.EDU Neil S. Millar Susan Wonnacott <p>Nicotinic acetylcholine (ACh) 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="">215</a>, <a href="">3</a>, <a href="">159</a>, <a href="">225</a>, <a href="">259</a>]. All nicotinic receptors are pentamers in which each of the five subunits contains 4 TM domains. Genes encoding a total of 17 subunits (&#945;1-10, &#946;1-4, &#947;, &#948; and &#949;) have been identified [<a href="">120</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="">159</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). Nicotinic ACh receptors 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 4 TM domains [<a href="">264</a>, <a href="">87</a>]; see also [<a href="">106</a>]). The high resolution crystal structure of the molluscan ACh 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="">35</a>]) and the crystal structure of the extracellular domain of the &#945;1 subunit bound to <a href="">&#945;-bungarotoxin</a> at 1.94&#194; resolution [<a href="">55</a>], has revealed the orthosteric binding site in detail (reviewed in [<a href="">215</a>, <a href="">120</a>, <a href="">39</a>, <a href="">198</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 &#946;(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="">96</a>, <a href="">93</a>, <a href="">159</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="">159</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="">159</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="">263</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="">159</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="">158</a>, <a href="">9</a>, <a href="">118</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="">143</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- see also [<a href="">46</a>]).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Transient Receptor Potential channels (TRP) in GtoPdb v.2021.3 2021-09-29T10:26:57+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 <div><p>The TRP superfamily of channels (<b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">159</a>, <a href="">997</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 TM 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="">679</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="">371</a>, <a href="">635</a>, <a href="">1064</a>, <a href="">236</a>]. The established, or potential, involvement of TRP channels in disease is reviewed in [<a href="">412</a>, <a href="">634</a>] and [<a href="">637</a>], together with a special edition of <i>Biochemica et Biophysica Acta</i> on the subject [<a href="">634</a>]. Additional disease related reviews, for pain [<a href="">585</a>], stroke [<a href="">1050</a>], sensation and inflammation [<a href="">919</a>], itch [<a href="">117</a>], and airway disease [<a href="">284</a>, <a href="">977</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="">751</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="">939</a>, <a href="">638</a>, <a href="">747</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="">268</a>]). TRPA1 activation of sensory neurons contribute to nociception [<a href="">382</a>, <a href="">829</a>, <a href="">555</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="">529</a>, <a href="">51</a>, <a href="">336</a>, <a href="">531</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="">23</a>, <a href="">51</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="">391</a>, <a href="">470</a>, <a href="">1005</a>, <a href="">1004</a>]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [<a href="">392</a>, <a href="">193</a>]. The electron cryo-EM structure of TRPA1 [<a href="">688</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="">261</a>, <a href="">726</a>, <a href="">15</a>, <a href="">4</a>, <a href="">84</a>, <a href="">410</a>, <a href="">687</a>, <a href="">60</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="">713</a>, <a href="">887</a>, <a href="">997</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="">15</a>] and [<a href="">411</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="">689</a>, <a href="">15</a>, <a href="">718</a>, <a href="">764</a>, <a href="">1037</a>, <a href="">141</a>, <a href="">675</a>, <a href="">55</a>, <a href="">142</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="">319</a>, <a href="">318</a>]. Activation of TRPC channels by lipids is discussed by [<a href="">60</a>]. Important progress has been recently made in TRPC pharmacology [<a href="">751</a>, <a href="">571</a>, <a href="">400</a>, <a href="">92</a>]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [<a href="">270</a>, <a href="">61</a>, <a href="">825</a>, <a href="">958</a>]. <br><br><b>TRPC1/C4/C5 subgroup</b><br> TRPC1 alone may not form a functional ion channel [<a href="">210</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="">1034</a>, <a href="">672</a>, <a href="">673</a>, <a href="">1035</a>, 496, <a href="">1075</a>, <a href="">1030</a>].<br><br><b>TRPC3/C6/C7 subgroup</b><br> All members are activated by diacylglycerol independent of protein kinase C stimulation [<a href="">319</a>].</p><heading>TRPM (melastatin) family</heading><p>Members of the TRPM subfamily (reviewed by [<a href="">252</a>, <a href="">318</a>, <a href="">689</a>, <a href="">1062</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="">368</a>, <a href="">657</a>]. TRPM3 (reviewed by [<a href="">663</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="">876</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="">662</a>, <a href="">875</a>]. TRPM3 may contribute to the detection of noxious heat [<a href="">947</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="">1018</a>]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [<a href="">219</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="">900</a>]. TRPM2 is involved in warmth sensation [<a href="">788</a>], and contributes to neurological diseases [<a href="">66</a>]. Recent study shows that 2'-deoxy-ADPR is an endogenous TRPM2 superagonist [<a href="">253</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="">997</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="">301</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="">546</a>]. Mutations are associated with conduction defects [<a href="">374</a>, <a href="">546</a>, <a href="">819</a>]. TRPM4 has been shown to be an important regulator of Ca<sup>2+</sup> entry in to mast cells [<a href="">924</a>] and dendritic cell migration [<a href="">43</a>]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [<a href="">494</a>] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [<a href="">471</a>]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [<a href="">226</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="">574</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="">54</a>, <a href="">161</a>, <a href="">205</a>] reviewed by [<a href="">941</a>, <a href="">516</a>, <a href="">420</a>, <a href="">599</a>]. </p><heading>TRPML (mucolipin) family</heading><p>The TRPML family [<a href="">729</a>, <a href="">1047</a>, <a href="">723</a>, <a href="">1008</a>, <a href="">173</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="">765</a>]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [<a href="">293</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="">729</a>, <a href="">639</a>]). </p><heading>TRPP (polycystin) family</heading><p>The TRPP family (reviewed by [<a href="">197</a>, <a href="">195</a>, <a href="">275</a>, <a href="">986</a>, <a href="">345</a>]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [<a href="">997</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="">317</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="">843</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="">926</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="">710</a>, <a href="">822</a>, <a href="">858</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="">786</a>]. The pharmacology of TRPV1 channels is discussed in detail in [<a href="">303</a>] and [<a href="">945</a>]. TRPV2 is probably not a thermosensor in man [<a href="">684</a>], but has recently been implicated in innate immunity [<a href="">503</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="">114</a>, <a href="">488</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="">982</a>, <a href="">185</a>, <a href="">601</a>, <a href="">248</a>]).</p></div> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Two-pore domain potassium channels (K<sub>2P</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Austin M. Baggetta Douglas A. Bayliss Gábor Czirják Péter Enyedi Steve A.N. Goldstein Florian Lesage Daniel L. Minor, Jr. Leigh D. Plant Francisco Sepúlveda <p>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-pore 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="">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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated calcium channels (Ca<sub>V</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 William A. Catterall Edward Perez-Reyes Terrance P. Snutch Jörg Striessnig <p>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="">127</a>] and <b>approved by the <u>NC-IUPHAR</u> Subcommittee on Ca<sup>2+</sup> channels [<a href="">70</a>]</b>. Most 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- to moderate-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-IV), each repeat having six transmembrane domains (S1-S6) and a pore-forming region between S5 and S6. Voltage-dependent gating is driven by the membrane spanning S4 segment, which contains highly conserved positive charges that respond to changes in membrane potential. All 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-&#948; subunits. The &#947; subunits have not been proven to associate with channels other than the &#945;1s skeletal muscle Ca<sub>v</sub>1.1 channel. The &#945;2-&#948;1 and &#945;2-&#948;2 subunits bind <a href="">gabapentin</a> and <a href="">pregabalin</a>.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated potassium channels (K<sub>v</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:57+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 <p>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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Voltage-gated sodium channels (Na<sub>V</sub>) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 William A. Catterall Alan L. Goldin Stephen G. Waxman <p>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="">177</a>]. &#945;-Subunits consist of four homologous domains (I-IV), each containing six transmembrane segments (S1-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="">274</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="">274</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="">144</a>] and approved by the <u>NC-IUPHAR</u> Subcommittee on sodium channels (Catterall <i>et al</i>., 2005, [<a href="">52</a>]).</b></p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## ZAC in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Paul Davies Tim G. Hales Anders A. Jensen John A. Peters <p>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="">2</a>, <a href="">3</a>, <a href="">4</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="">4</a>]. ZAC displays constitutive activity that can be blocked by <a href="">tubocurarine</a> and high concentrations of Ca<sup>2+</sup> [<a href="">4</a>]. Although denoted ZAC, the channel is more potently activated by <a href="">H<sup>+</sup></a> and <a href="">Cu<sup>2+</sup></a>, with greater and lesser efficacy than <a href="">Zn<sup>2+</sup></a>, respectively [<a href="">4</a>]. ZAC is present in the human, chimpanzee, dog, cow and opossum genomes, but is functionally absent from mouse, or rat, genomes [<a href="">2</a>, <a href="">3</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## 3A. Estrogen receptors in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Laurel Coons Kenneth S. Korach <p>Estrogen receptor (ER) activity regulates diverse physiological processes <i>via</i> transcriptional modulation of target genes [<a href="">1</a>]. 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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## 3C. 3-Ketosteroid receptors in GtoPdb v.2021.3 2021-09-29T10:26:57+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 J. Young <p>Steroid hormone receptors (<b>nomenclature as agreed by the <u>NC-IUPHAR</u> Subcommittee on Nuclear Hormone Receptors [<a href="">74</a>, <a href="">215</a>, <a href="">3</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>). For rodent GR and MR, the physiological ligand is corticosterone rather than cortisol.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Stephan Kellenberger Lachlan D. Rash <p>Acid-sensing ion channels (ASICs, <b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">45</a>, <a href="">2</a>, <a href="">3</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="">66</a>] and INaC [<a href="">68</a>] that have also been named BASICs, for bile acid-activated ion channels [<a href="">86</a>]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [<a href="">43</a>, <a href="">40</a>, <a href="">7</a>, <a href="">90</a>, <a href="">89</a>, <a href="">73</a>] to form proton-gated, voltage-insensitive, Na<sup>+</sup> permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [<a href="">42</a>, <a href="">85</a>, <a href="">45</a>, <a href="">65</a>, <a href="">23</a>]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASIC&#945;, BNaC2&#945;) [<a href="">80</a>], ASIC1b (ASIC&#946;, BNaC2&#946;) [<a href="">19</a>] and ASIC1b2 (ASIC&#946;2) [<a href="">75</a>]; note that ASIC1a is also permeable to Ca<sup>2+</sup>] and ASIC2 [termed ASIC2a (MDEG1, BNaC1&#945;, BNC1&#945;) [<a href="">63</a>, <a href="">81</a>, <a href="">39</a>] and ASIC2b (MDEG2, BNaC1&#946;) [<a href="">53</a>]] have been cloned and differ in the first third of the protein. 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="">79</a>] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [<a href="">55</a>]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [<a href="">1</a>, <a href="">41</a>, <a href="">33</a>, <a href="">51</a>]. ASIC channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) 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) (ASIC distribution is well reviewed in [<a href="">52</a>, <a href="">27</a>]). 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="">34</a>, <a href="">47</a>, <a href="">93</a>], responses to focal ischemia [<a href="">87</a>] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [<a href="">38</a>], as well as seizures [<a href="">94</a>] and pain [<a href="">85</a>, <a href="">28</a>, <a href="">29</a>, <a href="">13</a>, <a href="">31</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="">53</a>, <a href="">5</a>, <a href="">37</a>, <a href="">11</a>]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (<i>e.g.</i> <a href="">amiloride</a> at ENaCs, <a href="">ibuprofen</a> at COX enzymes) [<a href="">64</a>, <a href="">60</a>]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effect on heteromeric channels see the comments below.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Aquaporins in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Roslyn M. Bill Alex C. Conner Philip Kitchen Mootaz Salman <p>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="">16</a>]. Since the isolation and cloning of the first aquaporin (AQP1) [<a href="">20</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="">4</a>]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [<a href="">14</a>], and superaquaporins (AQP11 and 12) located within cells [<a href="">12</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, although this is controversial [<a href="">14</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) [26]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia. 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="">23</a>], Kitchen <i>et al.</i> (2105) [<a href="">14</a>]].<br><br> Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six TM helices and two half helices that constitute a seventh 'pseudotransmembrane domain' that surrounds a narrow water conducting channel [<a href="">16</a>]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [<a href="">16</a>] that may mediate the transport through AQP1. 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="">5</a>] and they are therefore excluded from the tables [see Tradtrantip <i>et al.</i> (2017) [<a href="">22</a>] for a review].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Yoshikatsu Kanai <p>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) [<a href="">1</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC28 and SLC29 families of nucleoside transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 James R. Hammond <p>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 [<a href="">1</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## ABCC subfamily in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Mary Vore <p>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="">7</a>, <a href="">2</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC8 family of sodium/calcium exchangers in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Jules Hancox <p>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="">PMCA</a>) and sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (<a href="">SERCA</a>), as well as the sodium/potassium/calcium exchangers (NKCX, <a href="">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 [<a href="">1</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC15 family of peptide transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 David T. Thwaites Tiziano Verri <p>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 [<a href="">3</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC23 family of ascorbic acid transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 James M. May <p>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="">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 [<a href="">1</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC36 family of proton-coupled amino acid transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Catriona M.H. Anderson David T. Thwaites <p>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="">18</a>]. PAT2 is expressed at the apical membrane of the renal proximal tubule [<a href="">6</a>] and at the plasma-membrane in brown/beige adipocytes [<a href="">20</a>]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [<a href="">11</a>]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references [<a href="">3</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC47 family of multidrug and toxin extrusion transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Ken-ichi Inui <p>These proton:organic cation exchangers are predicted to have 13 TM segments [<a href="">12</a>] and are suggested to be responsible for excretion of many drugs in the liver and kidneys [<a href="">1</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Eicosanoid turnover in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Angelo A. Izzo Jane A. Mitchell <p>Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue <a href="">arachidonic acid</a> and its metabolites. Arachidonic acid is thought primarily to derive from <a href="">phospholipase A2</a> action on membrane phosphatidylcholine, and may be re-cycled to form phospholipid through conjugation with <a href="">coenzyme A</a> and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly <a href="">CYP2J2</a>. Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Adenosine turnover in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Detlev Boison <p>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>).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs) in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Chen Yan <p>3',5'-Cyclic nucleotide phosphodiesterases (PDEs, 3',5'-cyclic-nucleotide 5'-nucleotidohydrolase), <a href=";search_string=">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=";search_string=">E.C.</a> CNPase) activity is associated with myelin formation in the development of the CNS.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Pattern recognition receptors in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Clare Bryant Tom P. Monie <p>Pattern Recognition Receptors (PRRs, [<a href="">104</a>]) (<b>nomenclature as agreed by <u>NC-IUPHAR</u> sub-committee on Pattern Recognition Receptors,</b> [<a href="">18</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="">Caspase 4</a> and <a href="">caspase 5</a> <br><br><b>Non-catalytic PRRs</b><br><a href="">Absent in melanoma (AIM)-like receptors</a> (ALRs)<br><a href="">C-type lectin-like receptors (CLRs)</a><br><a href="">Other pattern recognition receptors</a><br><a href="">Advanced glycosylation end-product specific receptor</a> (RAGE)<br></p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Tumour necrosis factor (TNF) receptor family in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 David MacEwan <p>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="">5</a>, <a href="">6</a>, <a href="">49</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## SLC51 family of steroid-derived molecule transporters in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Paul A. Dawson <p>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="">2</a>, <a href="">5</a>, <a href="">1</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="">6</a>]. Bile acid transport is suggested to be facilitative and independent of sodium, potassium, chloride ions or protons [<a href="">5</a>, <a href="">2</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="">2</a>, <a href="">5</a>, <a href="">6</a>]. OST&#945;/OST&#946;-mediated transport of bile salts is inhibited by <a href="">clofazimine</a> [<a href="">10</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="">8</a>]. Both proteins function in solute transport [<a href="">8</a>, <a href="">4</a>]. Inherited mutations in OST&#945; and OST&#946; are associated with liver disease and congenital diarrhea in children [<a href="">9</a>, <a href="">7</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Chemerin receptors in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Anthony P. Davenport Amy E. Monaghan <p>Nomenclature for the chemerin receptors is presented as <b> recommended by <u>NC-IUPHAR</u> [<a href="">15</a>, <a href="">43</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="">43</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="">45</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Succinate receptor in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Anthony P. Davenport Julien Hanson Wen Chiy Liew <span><b>Nomenclature as recommended by <u>NC-IUPHAR</u> [<a href="">8</a>]</b>. The Succinate receptor was 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 the immune response.</span> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Ceramide turnover in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Anthony H. Futerman <p>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="">dihydrosphingosine</a>. 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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Phosphatidylinositol kinases in GtoPdb v.2021.3 2021-09-29T10:26:57+01:00 Mohib Uddin <div><p>Phosphatidylinositol may be phosphorylated at either 3- or 4- positions on the inositol ring by PI 3-kinases or PI 4-kinases, respectively.</p><heading>Phosphatidylinositol 3-kinases</heading><p>Phosphatidylinositol 3-kinases (PI3K, provisional nomenclature) catalyse the introduction of a phosphate into the 3-position of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) or phosphatidylinositol 4,5-bisphosphate (PIP<sub>2</sub>). There is evidence that PI3K can also phosphorylate serine/threonine residues on proteins. In addition to the classes described below, further serine/threonine protein kinases, including <a href="!/hgnc_id/HGNC:795">ATM</a> (<a href="">Q13315</a>) and <a href="!/hgnc_id/HGNC:3942">mTOR</a> (<a href="">P42345</a>), have been described to phosphorylate phosphatidylinositol and have been termed PI3K-related kinases. Structurally, PI3Ks have common motifs of at least one C2, calcium-binding domain and helical domains, alongside structurally-conserved catalytic domains. <a href="">wortmannin</a> and <a href="">LY 294002</a> are widely-used inhibitors of PI3K activities. <a href="">wortmannin</a> is irreversible and shows modest selectivity between Class I and Class II PI3K, while LY294002 is reversible and selective for Class I compared to Class II PI3K.</p><p><b>Class I PI3Ks</b> (EC phosphorylate phosphatidylinositol 4,5-bisphosphate to generate phosphatidylinositol 3,4,5-trisphosphate and are heterodimeric, matching catalytic and regulatory subunits. Class IA PI3Ks include p110&#945;, p110&#946; and p110&#948; catalytic subunits, with predominantly p85 and p55 regulatory subunits. The single catalytic subunit that forms Class IB PI3K is p110&#947;. Class IA PI3Ks are more associated with receptor tyrosine kinase pathways, while the Class IB PI3K is linked more with GPCR signalling.</p><p><b>Class II PI3Ks</b> (EC phosphorylate phosphatidylinositol to generate phosphatidylinositol 3-phosphate (and possibly phosphatidylinositol 4-phosphate to generate phosphatidylinositol 3,4-bisphosphate). Three monomeric members exist, PI3K-C2&#945;, &#946; and &#946;, and include Ras-binding, Phox homology and two C2 domains.</p><p>The only <b>class III PI3K</b> isoform (EC is a heterodimer formed of a catalytic subunit (VPS34) and regulatory subunit (VPS15).</p><heading>Phosphatidylinositol 4-kinases</heading><p>Phosphatidylinositol 4-kinases (EC generate phosphatidylinositol 4-phosphate and may be divided into higher molecular weight type III and lower molecular weight type II forms.</p></div> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Endocannabinoid turnover in GtoPdb v.2021.3 2021-09-29T10:26:56+01:00 Stephen P.H. Alexander Patrick Doherty Christopher J. Fowler Jürg Gertsch Mario van der Stelt <p>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="">28</a>]. <a href="">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="">17</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="">70</a>]). A transacylation enzyme which forms <i>N</i>-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, <a href="!/hgnc_id/HGNC:24791"><i>PLA2G4E</i></a> (<a href="">Q3MJ16</a>) [<a href="">62</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="">5</a>, <a href="">23</a>, <a href="">72</a>].</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## NADPH oxidases in GtoPdb v.2021.3 2021-09-29T10:26:56+01:00 Albert van der Vliet <p>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="">9</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.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Receptor guanylyl cyclase (RGC) family in GtoPdb v.2021.3 2021-09-29T10:26:56+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 <p>The mammalian genome encodes seven guanylyl cyclases, GC-A to GC-G, that are homodimeric transmembrane receptors activated by a diverse range of endogenous ligands. These enzymes convert <a href="">guanosine-5'-triphosphate</a> to the intracellular second messenger cyclic guanosine-3',5'-monophosphate (<a href="">cyclic GMP</a>). GC-A, GC-B and GC-C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC-D and GC-G are found in the olfactory neuropepithelium and Grueneberg ganglion of rodents, respectively. GC-E and GC-F are expressed in retinal photoreceptors.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## E3 ubiquitin ligase components in GtoPdb v.2021.3 2021-09-29T10:26:56+01:00 Elena Faccenda Robert Layfield <p>Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [<a href="">19</a>]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction.<br> E3 ubiquitin ligases, of which there are &gt;600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement## Coronavirus (CoV) proteins in GtoPdb v.2021.3 2021-09-29T10:26:56+01:00 Stephen P.H. Alexander Jonathan K. Ball Theocharis Tsoleridis <p>Coronaviruses are large, often spherical, enveloped, single-stranded positive-sense RNA viruses, ranging in size from 80-220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS-CoV was identified as the causative agent in an outbreak in 2002-2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS-CoV-2 emerged in 2019-2020. SARS-CoV-2 is the virus responsible for the infectious disease termed COVID-19 (<a href="" target="_blank">WHO Technical Guidance 2020</a>).</p> 2021-09-02T00:00:00+01:00 ##submission.copyrightStatement##