GPCR, family 3, vomeronasal receptor, type 2 (GPCR_3_vmron_rcpt_2)
Type: Family

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 . 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 . 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) . 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 . 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 .

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 . 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 . As these receptors regulate many important physiological processes they are potentially promising targets for drug development.

Pheromones have evolved in all animal phyla, to signal sex and dominance status, and are responsible for stereotypical social and sexual behaviour among members of the same species. In mammals, these chemical signals are believed to be detected primarily by the vomeronasal organ (VNO), a chemosensory organ located at the base of the nasal septum . The VNO is present in most amphibia, reptiles and non-primate mammals but is absent in birds, adult catarrhine monkeys and apes . An active role for the human VNO in the detection of pheromones is disputed; the VNO is clearly present in the foetus but appears to be atrophied or absent in adults. Three distinct families of putative pheromone receptors have been identified in the vomeronasal organ (V1Rs, V2Rs and V3Rs). All are G protein-coupled receptors but are only distantly related to the receptors of the main olfactory system, highlighting their different role .

The V2 receptors are members of GPCR family 3 and have close similarity to the extracellular calcium-sensing receptors . Rodents appear to have around 100 functional V2 receptors and many pseudogenes . These receptors are expressed in the basal regions of VNO, where they couple to G proteins to mediate inositol trisphosphate responses . Homologues have also been identified in fish , and the ligand specificity of one such receptor has been determined: a receptor from goldfish olfactory epithelium has been reported to bind basic amino acids, which are odorants for fish .