The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

Alexander SPH, Arthur Christopoulos, Anthony P. Davenport, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA, Abbracchio MP, Abraham G, Alexander I. Agoulnik, Alexander W, Al-Hosaini K, Magnus Bäck, Baker JG, Barnes NM, Bathgate R, Beaulieu JM, Beck-Sickinger AG, Behrens M, Bernstein KE, Bettler B, Birdsall NJM, Blaho VA, Boulay F, Bousquet C, Bräuner-Osborne H, Burnstock G, Caló G, Justo P. Castaño, Catt KJ, Ceruti S, Chazot P, Chiang N, Chini B, Chun J, Cianciulli A, Civelli O, Clapp LH, Couture R, Cox HM, Csaba Z, Dahlgren C, Dent G, Douglas SD, Dournaud P, Eguchi S, Escher E, Filardo EJ, Fong T, Fumagalli M, Gainetdinov RR, Garelja ML, de Gasparo M, Gerard C, Gershengorn M, Gobeil F, Goodfriend TL, Goudet C, Grätz L, Gregory KJ, Gundlach AL, Hamann J, Hanson J, Hauger RL, Hay DL, Heinemann A, Herr DR, Hollenberg MD, Holliday ND, Horiuchi M, Hoyer D, Hunyady L, Husain A, IJzerman AP, Inagami T, Jacobson KA, Jensen RT, Jockers R, Jonnalagadda D, Karnik SS, Kaupmann K, Kemp J, Kennedy C, Kihara Y, Kitazawa T, Kozielewicz P, Kreienkamp HJ, Kukkonen JP, Langenhan T, Larhammar D, Leach K, Lecca D, Lee JD, Leeman SE, Leprince J, Li XX, Lolait SJ, Lupp A, Macrae R, Maguire JJ, Malfacini D, Mazella J, McArdle CA, Melmed S, Michel MC, Miller LJ, Mitolo V, Mouillac B, Müller CE, Murphy PM, Nahon JL, Ngo T, Norel X, Nyimanu D, O'Carroll AM, Offermanns S, Panaro MA, Parmentier M, Pertwee RG, Jean-Philippe Pin, PROSSNITZ ERIC R, Quinn M, Ramachandran R, Ray M, Reinscheid RK, P Rondard, Rovati GE, Ruzza C, Sanger GJ, Schöneberg T, Schulte G, Schulz S, Segaloff DL, Serhan CN, Singh KD, Smith CM, Stoddart LA, Sugimoto Y, Summers R, Tan VP, Thal DM, Thomas WW, Timmermans PBMWM, Tirupula K, Toll L, Tulipano G, Unal H, Unger T, Valant C, Vanderheyden P, Vaudry D, Vaudry H, Vilardaga JP, Walker CS, Wang JM, Ward DT, Wester HJ, Willars GB, Williams TL, Woodruff TM, Yao C, Ye RD
British journal of pharmacology · 2023 · doi:10.1111/bph.16177 · PMID:38123151 · PMC13324819
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This publication provides a comprehensive overview of G protein-coupled receptors, detailing properties of approximately 1800 drug targets and 6000 interactions with 3900 ligands to serve as an official IUPHAR classification resource.

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This paper provides a comprehensive overview of G protein-coupled receptors, detailing their classification, pharmacology, and structural characteristics across various families including orphan receptors, taste receptors, serotonin receptors, and muscarinic acetylcholine receptors. It highlights specific ligand interactions, such as the binding modalities of ergotamine to 5-HT1B receptors and the allosteric modulation of muscarinic subtypes, while noting limitations in ligand selectivity for certain receptor types. The text also addresses pseudogenes and the functional diversity arising from alternative splicing and RNA editing within these receptor systems. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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Ghrelin

G protein-coupled receptors → Ghrelin receptor Overview : The ghrelin receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [ 533 ]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor ( GHRL , Q9UBU3 ). The human gene encoding the precursor peptide has 83% sequence homology to rat preproghrelin, although the mature peptides from rat and human differ by only two amino acids [ 1673 ]. Alternative splicing results in the formation of a second peptide, [des-Gln 14 ]ghrelin ( GHRL , Q9UBU3 ) with equipotent biological activity [ 1055 ]. A unique post-translational modification (octanoylation of Ser 3 , catalysed by ghrelin Ο-acyltransferase ( MBOAT4 , Q96T53 ) [ 2866 ] 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 [ 1328 ]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [ 158 ], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin ( GHRL , Q9UBU3 ) function [ 1044 ]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [ 787 , 1588 ] inhibits ghrelin receptor-induced GH secretion and food intake [ 787 ]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [ 1637 ]. In cell systems, the ghrelin receptor is constitutively active [ 1045 ], 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 [ 1983 ]. Comments : [des-octanoyl]ghrelin ( GHRL , Q9UBU3 ) has been shown to bind (as [ 125 I]Tyr 4 -des-octanoyl-ghrelin ) and have effects in the cardiovascular system [ 157 ], which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been identified ( [D-Arg 1 , D-Phe 5 , D-Trp 7,9 , Leu 11 ]substance P , p D 2 8.3; [ 1042 ]). Ulimorelin , described as a ghrelin receptor agonist (p K i 7.8 and p D 2 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically discriminating the orexigenic and gastrointestinal actions of ghrelin ( GHRL , Q9UBU3 ) from the release of growth hormone [ 724 ]. Similar discrimination of ghrelin receptor mediated physiological functions can be obtained by activation of distinct signaling pathways [ 1708 ]. A number of selective antagonists have been reported, including peptidomimetic [ 1817 ] and non-peptide small molecules including GSK1614343 [ 2004 , 2020 , 2242 ].

Odorant

Odorant receptors are G protein-coupled receptors responsible for the detection of generally volatile compounds associated with olfaction. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of olfactory receptors at HGNC , and curated by HORDE and ORDB .

Section

G protein-coupled receptors → VIP and PACAP receptors Overview : Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [ 950 , 951 ]) are activated by the endogenous peptides VIP ( VIP , P01282 ), PACAP-38 ( ADCYAP1 , P18509 ), PACAP-27 ( ADCYAP1 , P18509 ), peptide histidine isoleucineamide ( PHI {Mouse, Rat}), peptide histidine methionineamide ( PHM ( VIP , P01282 )) and peptide histidine valine ( PHV ( VIP , P01282 )). VPAC 1 and VPAC 2 receptors display comparable affinity for the PACAP peptides, PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ), and VIP ( VIP , P01282 ), whereas PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ) are > 100 fold more potent than VIP ( VIP , P01282 ) as agonists of most isoforms of the PAC 1 receptor. However, one splice variant of the human PAC 1 receptor has been reported to respond to PACAP-38 ( ADCYAP1 , P18509 ), PACAP-27 ( ADCYAP1 , P18509 ) and VIP ( VIP , P01282 ) with comparable affinity [ 529 ]. PG 99-465 [ 1789 ] has been used as a selective VPAC 2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC 1 and PAC 1 receptors [ 581 ]. The selective PAC 1 receptor agonist maxadilan , was extracted from the salivary glands of sand flies ( Lutzomyia longipalpis ) and has no sequence homology to VIP ( VIP , P01282 ) or the PACAP peptides [ 1805 ]. Two deletion variants of maxadilan , M65 [ 2624 ] and Max.d.4 [ 1806 ] have been reported to be PAC 1 receptor antagonists, but these peptides have not been extensively characterised. Comments : Subtypes of PAC 1 receptors have been proposed based on tissue differences in the potencies of PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ); these might result from differences in G protein coupling and second messenger mechanisms [ 2659 ], or from alternative splicing of PAC 1 receptor mRNA [ 2442 ].

Pseudogenes

A number of pseudogenes have been identified in the human genome, which, in some cases, have a shared ancestry with functional G protein-coupled receptors in other species, including rats and mice. A curated list includes: ADGRE4P , GNRHR2 , GPR79 , HTR5BP , NPY6R , TAAR3P , TAAR4P , TAAR7P , TAS2R12P , TAS2R15P , TAS2R18P , TAS2R2P , TAS2R62P , TAS2R63P , TAS2R64P , TAS2R67P , TAS2R68P , TAS2R6P . A more detailed listing containg further information can be viewed here .

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