- Advanced search
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) . 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 [8,10], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs  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"  divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:
Glutamate family (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 .
Rhodopsin family (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).
Adhesion family 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 .
Frizzled family 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)) .
|Family||Class A||Class B (Secretin)||Class C (Glutamate)||Adhesion||Frizzled|
|Receptors with known ligands||197a||15||12||0||11|
|Orphans||87 (54)a||-||8 (1)a||26 (6)a||0|
|Sensory (vision)||10d opsins||-||-||-||-|
|Sensory (taste)||30c taste 2||-||3c taste 1||-||-|
|Sensory (pheromone)||5c vomeronasal 1||-||-||-||-|
Much of our current understanding of the structure and function of GPCRs is the result of pioneering work on the visual pigment rhodopsin and on the β2 adrenoceptor, the latter culminating in the award of the 2012 Nobel Prize in chemistry to Robert Lefkowitz and Brian Kobilka [3,5].
Guide to Immunopharmacology view: OFF
1. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev., 65 (3): 967-86. [PMID:23686350]
2. Harmar AJ. (2001) Family-B G-protein-coupled receptors. Genome Biol., 2 (12): REVIEWS3013. [PMID:11790261]
3. Kobilka B. (2013) The structural basis of G-protein-coupled receptor signaling (Nobel Lecture). Angew. Chem. Int. Ed. Engl., 52 (25): 6380-8. [PMID:23650120]
4. Kolakowski Jr LF. (1994) GCRDb: a G-protein-coupled receptor database. Recept. Channels, 2 (1): 1-7. [PMID:8081729]
5. Lefkowitz RJ. (2013) A brief history of G-protein coupled receptors (Nobel Lecture). Angew. Chem. Int. Ed. Engl., 52 (25): 6366-78. [PMID:23650015]
6. Mombaerts P. (2004) Genes and ligands for odorant, vomeronasal and taste receptors. Nat. Rev. Neurosci., 5 (4): 263-78. [PMID:15034552]
7. Olender T, Lancet D, Nebert DW. (2008) Update on the olfactory receptor (OR) gene superfamily. Hum. Genomics, 3 (1): 87-97. [PMID:19129093]
8. Overington JP, Al-Lazikani B, Hopkins AL. (2006) How many drug targets are there?. Nat Rev Drug Discov, 5 (12): 993-6. [PMID:17139284]
9. Prömel S, Langenhan T, Araç D. (2013) Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins. Trends Pharmacol. Sci., 34 (8): 470-8. [PMID:23850273]
10. Rask-Andersen M, Masuram S, Schiöth HB. (2014) The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol., 54: 9-26. [PMID:24016212]
11. Schiöth HB, Fredriksson R. (2005) The GRAFS classification system of G-protein coupled receptors in comparative perspective. Gen. Comp. Endocrinol., 142 (1-2): 94-101. [PMID:15862553]
12. Terakita A. (2005) The opsins. Genome Biol., 6 (3): 213. [PMID:15774036]
Database page citation:
G protein-coupled receptors. Accessed on 25/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=694.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Davenport AP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol. 172: 5744-5869.