InterPro domain: IPR000337

GPCR family 3 receptors (also known as family C) are structurally similar to other GPCRs, but do not show any significant sequence similarity and thus represent a distinct group. Structurally they are composed of four elements; an N-terminal signal sequence; a large hydrophilic extracellular agonist-binding region containing several conserved cysteine residues which could be involved in disulphide bonds; a shorter region containing seven transmembrane domains; and a C-terminal cytoplasmic domain of variable length [ 1 ]. Family 3 members include the metabotropic glutamate receptors, the extracellular calcium-sensing receptors, the gamma-amino-butyric acid (GABA) type B receptors, and the vomeronasal type-2 receptors [ 2 , 3 , 4 , 5 ]. As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups [ 6 ]. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [ 7 ]. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [ 8 , 8 , 9 , 10 , 11 ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice [ 12 ]. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [ 12 ].

1. Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors. J. Pharmacol. Exp. Ther. 8, 169-84
2. A family of metabotropic glutamate receptors. Neuron 8, 169-79
3. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 366, 575-80
4. Coexpression of full-length gamma-aminobutyric acid(B) (GABA(B)) receptors with truncated receptors and metabotropic glutamate receptor 4 supports the GABA(B) heterodimer as the functional receptor. Proc. Natl. Acad. Sci. U.S.A. 293, 460-7
5. A new multigene family of putative pheromone receptors. Neuron 19, 371-9
6. The G protein-coupled receptor repertoires of human and mouse. Recept. Channels 100, 4903-8
7. Fingerprinting G-protein-coupled receptors. Protein Eng. 7, 195-203
8. GCRDb: a G-protein-coupled receptor database. Pharmacol. Rev. 2, 1-7
9. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Nucleic Acids Res. 57, 279-88
10. IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels. Genomics 37, D680-5
11. Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Annu. Rev. Pharmacol. Toxicol. 88, 263-73
12. G protein-coupled receptor deorphanizations. null 53, 127-46