IUPHAR/BPS Guide to Pharmacology CITE 2024-02-27T14:57:48+00:00 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> Adrenoceptors in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 Jillian G. Baker Poornima Balaji Richard A. Bond David B. Bylund Douglas C. Eikenburg Robert M. Graham J. Paul Hieble Rebecca Hills Martin C. Michel Kenneth P. Minneman Sergio Parra Dianne Perez Roger Summers <span><b>The nomenclature of the Adrenoceptors has been agreed by the <u>NC-IUPHAR</u> Subcommittee on Adrenoceptors [<a href="">64</a>, <a href="">194</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="">33</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="">332</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="">528</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="">197</a>].</span> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Prolactin-releasing peptide receptor in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 Vanni Caruso Rebecca Hills Malin Lagerstrom Tatsushi Onaka Helgi Schiƶth <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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## 5-HT<sub>3</sub> receptors in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Nicotinic acetylcholine receptors (nACh) in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Transient Receptor Potential channels (TRP) in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 Nathaniel T. Blair Ana I. Caceres Ingrid Carvacho Dipayan Chaudhuri David E. Clapham Katrien De Clerq Markus Delling Julia F. Doerner Lu Fan Christian M. Grimm Kotdaji Ha Meiqin Hu Sairam V. Jabba Sven E. Jordt David Julius Kristopher T Kahle Boyi Liu Qiang Liu David McKemy Bernd Nilius Elena Oancea Grzegorz Owsianik Antonio Riccio Rajan Sah; Stephanie C. Stotz Jinbin Tian Dan Tong Joris Vriens Long-Jun Wu Haoxing Xu Fan Yang Wei Yang Lixia Yue Michael X. Zhu <div><p>The TRP superfamily of channels (<b>nomenclature as agreed by <u>NC-IUPHAR</u> [<a href="">176</a>, <a href="">1075</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="">730</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="">401</a>, <a href="">686</a>, <a href="">1158</a>, <a href="">256</a>]. The established, or potential, involvement of TRP channels in disease [<a href="">1129</a>] is reviewed in [<a href="">448</a>, <a href="">685</a>], [<a href="">688</a>] and [<a href="">464</a>], together with a special edition of <i>Biochemica et Biophysica Acta</i> on the subject [<a href="">685</a>]. Additional disease related reviews, for pain [<a href="">633</a>], stroke [<a href="">1138</a>], sensation and inflammation [<a href="">990</a>], itch [<a href="">130</a>], and airway disease [<a href="">310</a>, <a href="">1054</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="">806</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="">1011</a>, <a href="">689</a>, <a href="">802</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="">293</a>]). TRPA1 activation of sensory neurons contribute to nociception [<a href="">414</a>, <a href="">891</a>, <a href="">602</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="">575</a>, <a href="">60</a>, <a href="">365</a>, <a href="">577</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="">26</a>, <a href="">60</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="">424</a>, <a href="">511</a>, <a href="">1084</a>, <a href="">1083</a>]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [<a href="">425</a>, <a href="">212</a>]. The electron cryo-EM structure of TRPA1 [<a href="">741</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="">284</a>, <a href="">779</a>, <a href="">18</a>, <a href="">4</a>, <a href="">94</a>, <a href="">446</a>, <a href="">740</a>, <a href="">70</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="">766</a>, <a href="">955</a>, <a href="">1075</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="">18</a>] and [<a href="">447</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="">742</a>, <a href="">18</a>, <a href="">771</a>, <a href="">821</a>, <a href="">1124</a>, <a href="">157</a>, <a href="">726</a>, <a href="">64</a>, <a href="">158</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="">347</a>, <a href="">346</a>]. Activation of TRPC channels by lipids is discussed by [<a href="">70</a>]. Important progress has been recently made in TRPC pharmacology [<a href="">806</a>, <a href="">619</a>, <a href="">436</a>, <a href="">102</a>, <a href="">852</a>, <a href="">191</a>, <a href="">291</a>]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [<a href="">295</a>, <a href="">71</a>, <a href="">886</a>, <a href="">1034</a>, <a href="">1028</a>, <a href="">154</a>, <a href="">103</a>, <a href="">561</a>, <a href="">914</a>, <a href="">409</a>]. <br><br><b>TRPC1/C4/C5 subgroup</b><br> TRPC1 alone may not form a functional ion channel [<a href="">229</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="">1117</a>, <a href="">723</a>, <a href="">724</a>, <a href="">1118</a>, 539, <a href="">1171</a>, <a href="">1112</a>].<br><br><b>TRPC3/C6/C7 subgroup</b><br> All members are activated by diacylglycerol independent of protein kinase C stimulation [<a href="">347</a>].</p><heading>TRPM (melastatin) family</heading><p>Members of the TRPM subfamily (reviewed by [<a href="">275</a>, <a href="">346</a>, <a href="">742</a>, <a href="">1154</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="">398</a>, <a href="">708</a>]. TRPM3 (reviewed by [<a href="">714</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="">943</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="">713</a>, <a href="">942</a>]. TRPM3 may contribute to the detection of noxious heat [<a href="">1020</a>]. <br><br><b>TRPM2</b><br>TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [<a href="">972</a>] and cyclic ADPR (<a href="">cADPR</a>) [<a href="">1121</a>]. As for many ion channels, PI(4,5)P2 must also be present [<a href="">1112</a>]. Numerous splice variants of <i>TRPM2</i> exist which differ in their activation mechanisms [<a href="">239</a>]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca<sup>2+</sup> binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca<sup>2+</sup> binding that induces conformational changes leading the ADPR-bound closed channel to open [<a href="">387</a>, <a href="">1030</a>]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [<a href="">1123</a>]. TRPM2 is involved in warmth sensation [<a href="">849</a>], and contributes to several diseases [<a href="">76</a>]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [<a href="">1167</a>]. Activation of TRPM2 in macrophages promotes atherosclerosis [<a href="">1168</a>, <a href="">1150</a>]. Moreover, silica nanoparticles induce lung inflammation in mice <i>via</i> ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [<a href="">1031</a>]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [<a href="">1140</a>, <a href="">1142</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="">1075</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="">327</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="">593</a>]. Mutations are associated with conduction defects [<a href="">404</a>, <a href="">593</a>, <a href="">880</a>]. TRPM4 has been shown to be an important regulator of Ca<sup>2+</sup> entry in to mast cells [<a href="">995</a>] and dendritic cell migration [<a href="">52</a>]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [<a href="">537</a>] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [<a href="">513</a>]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [<a href="">246</a>]. <br><br><b>TRPM6/7 subgroup</b><br>TRPM6 and 7 combine channel and enzymatic activities (&#8216;chanzymes&#8217;) [<a href="">172</a>]. 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. PIP2 is required for TRPM6 and TRPM7 activation [<a href="">811</a>, <a href="">1080</a>]. When either gene is deleted in mice, the result is embryonic lethality [<a href="">413</a>, <a href="">1068</a>]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [<a href="">479</a>, <a href="">480</a>]. 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="">622</a>]. The putative metal transporter proteins <a href="!/group/1801" target="_blank">CNNM1-4</a> interact with TRPM7 and regulate TRPM7 channel activity [<a href="">40</a>, <a href="">467</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="">63</a>, <a href="">178</a>, <a href="">224</a>] reviewed by [<a href="">1013</a>, <a href="">562</a>, <a href="">457</a>, <a href="">649</a>]. Direct chemical agonists include menthol and <a href="">icilin</a>[<a href="">1089</a>]. Besides, <a href="">linalool</a> can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [<a href="">68</a>]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [<a href="">512</a>], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP<sub>2</sub>-dependent gated pathways [<a href="">1114</a>]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [<a href="">194</a>]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4&#945; in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [<a href="">556</a>]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [<a href="">12</a>]. A cyclic peptide DeC&#8208;1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [<a href="">9</a>]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and &#946;-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [<a href="">732</a>]. </p><heading>TRPML (mucolipin) family</heading><p>The TRPML family [<a href="">783</a>, <a href="">1135</a>, <a href="">776</a>, <a href="">1087</a>, <a href="">190</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="">823</a>]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [<a href="">319</a>, <a href="">147</a>, <a href="">878</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="">783</a>, <a href="">690</a>]). </p><heading>TRPP (polycystin) family</heading><p>The TRPP family (reviewed by [<a href="">216</a>, <a href="">214</a>, <a href="">300</a>, <a href="">1064</a>, <a href="">374</a>]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [<a href="">1075</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="">345</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="">906</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="">997</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="">763</a>, <a href="">883</a>, <a href="">923</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="">845</a>]. The pharmacology of TRPV1 channels is discussed in detail in [<a href="">329</a>] and [<a href="">1018</a>]. TRPV2 is probably not a thermosensor in man [<a href="">736</a>], but has recently been implicated in innate immunity [<a href="">547</a>]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [<a href="">204</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="">127</a>, <a href="">530</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="">1060</a>, <a href="">205</a>, <a href="">651</a>, <a href="">270</a>]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [<a href="">1059</a>].</p></div> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Aquaporins in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## SLC23 family of ascorbic acid transporters in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Hydrolases & Lipases in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 Stephen P.H. Alexander Patrick Doherty David Fairlie Christopher J. Fowler Christopher M. Overall Neil Rawlings Christopher Southan Anthony J. Turner <p>Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 <a href="" target="_blank">(P23141</a>), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins.</p> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## NADPH oxidases in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## E3 ubiquitin ligase components in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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="">48</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. <br>E3 ligases are being exploited as pharmacological targets to facilitate targeted protein degradation (TPD), as an alternative to small molecule inhibitors [<a href="">5</a>], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues.</p> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement## Coronavirus (CoV) proteins in GtoPdb v.2023.3 2024-02-27T14:57:48+00:00 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> 2023-11-29T00:00:00+00:00 ##submission.copyrightStatement##