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Review
. 2019 Dec;176 Suppl 1(Suppl 1):S21-S141.
doi: 10.1111/bph.14748.

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors

Stephen P H Alexander  1 , Arthur Christopoulos  2 , Anthony P Davenport  3 , Eamonn Kelly  4 , Alistair Mathie  5 , John A Peters  6 , Emma L Veale  5 , Jane F Armstrong  7 , Elena Faccenda  7 , Simon D Harding  7 , Adam J Pawson  7 , Joanna L Sharman  7 , Christopher Southan  7 , Jamie A Davies  7 ; CGTP Collaborators
Collaborators, Affiliations
Review

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein-coupled receptors

Stephen P H Alexander et al. Br J Pharmacol. 2019 Dec.

Abstract

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 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/10.1111/bph.14748. 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-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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Conflict of interest statement

Overview

G protein‐coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term "7TM receptor" is commonly used interchangeably with "GPCR", although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N‐terminus, an intracellular C‐terminus and seven hydrophobic transmembrane domains (TM1‐TM7) linked by three extracellular loops (ECL1‐ECL3) and three intracellular loops (ICL1‐ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (˜400), taste (33), light perception (10) and pheromone signalling (5) [http://www.ncbi.nlm.nih.gov/pubmed/15034552?dopt=AbstractPlus]. The remaining 350 non‐sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/24016212?dopt=AbstractPlus], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [http://www.ncbi.nlm.nih.gov/pubmed/8081729?dopt=AbstractPlus] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A (rhodopsin‐like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme "GRAFS" [http://www.ncbi.nlm.nih.gov/pubmed/15862553?dopt=AbstractPlus] divides vertebrate GPCRs into five classes, overlapping with the A‐F nomenclature, viz:

Glutamate family (http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=C), which includes metabotropic glutamate receptors, a calcium‐sensing receptor and GABAB receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [http://www.ncbi.nlm.nih.gov/pubmed/15034552?dopt=AbstractPlus].

Rhodopsin family (http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors).

http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=Adhesion GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N‐termini that are autoproteolytically cleaved from their 7TM domains at a conserved "GPCR proteolysis site" (GPS) which lies within a much larger (320 residue) "GPCR autoproteolysis‐inducing" (GAIN) domain, an evolutionary ancient mofif also found in polycystic kidney disease 1 (PKD1)‐like proteins, which has been suggested to be both required and sufficient for autoproteolysis [http://www.ncbi.nlm.nih.gov/pubmed/23850273?dopt=AbstractPlus].

http://www.guidetopharmacology.org/GRAC/GPCRListForward?class=Frizzled consists of 10 Frizzled proteins (FZD(1‐10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27‐141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon‐like peptides (GLP‐1, GLP‐2), glucose‐dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase‐activating polypeptide (PACAP) and growth‐hormone‐releasing hormone (GHRH)) [http://www.ncbi.nlm.nih.gov/pubmed/11790261?dopt=AbstractPlus].

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