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) [4]. 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 [6,8], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [3] 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" [9] 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 GABA_B 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 [4].

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 [7].

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)) [2].

GPCR families

Family	Class A	Class B (Secretin)	Class C (Glutamate)	Adhesion	Frizzled
Receptors with known ligands	197	15	12	0	11
Orphans	87 (54)a	-	8 (1)a	33 (7)a	0
Sensory (olfaction)	390b,c	-	-	-	-
Sensory (vision)	10d opsins	-	-	-	-
Sensory (taste)	30c taste 2	-	3c taste 1	-	-
Sensory (pheromone)	5c vomeronasal 1	-	-	-	-
Total	719	15	23	33	11

^aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [1]; ^b[5]; ^c[4]; ^d[10].

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.

Odorant receptors
Odorant receptors are also seven-transmembrane spanning G protein-coupled receptors, responsible for the detection of odorant, 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 odorant receptors at HGNC, and curated by HORDE and ORDB.

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* Key recommended reading is highlighted with an asterisk

* Kenakin T. (2018) Is the Quest for Signaling Bias Worth the Effort?. Mol Pharmacol, 93 (4): 266-269. [PMID:29348268]

* Michel MC, Charlton SJ. (2018) Biased Agonism in Drug Discovery-Is It Too Soon to Choose a Path?. Mol Pharmacol, 93 (4): 259-265. [PMID:29326242]

* Roth BL, Irwin JJ, Shoichet BK. (2017) Discovery of new GPCR ligands to illuminate new biology. Nat Chem Biol, 13 (11): 1143-1151. [PMID:29045379]

* Sriram K, Insel PA. (2018) G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?. Mol Pharmacol, 93 (4): 251-258. [PMID:29298813]

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8. 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]

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