vomeronasal type-2 pheromone receptors, amino acid-sensing receptors and closely related proteins; member of the class C family of seven-transmembrane G protein-coupled receptors
This group is composed of vomeronasal type-2 pheromone receptors (V2Rs), a subgroup of broad-spectrum amino-acid sensing receptors including calcium-sensing receptor (CaSR) and GPRC6A, as well as their closely related proteins. Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are co-expressed in the basal layer of the vomeronsal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are co-expressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, producing the second messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones. CaSR is a widely expressed GPCR that is involved in sensing small changes in extracellular levels of calcium ion to maintain a constant level of the extracellular calcium via modulating the synthesis and secretion of calcium regulating hormones, such as parathyroid hormone (PTH), in order to regulate Ca(2+)transport into or out of the extracellular fluid via kidney, intestine, and/or bone. For instance, when Ca2+ is high, CaSR downregulates PTH synthesis and secretion, leading to an increase in renal Ca2+ excretion, a decrease in intestinal Ca2+ absorption, and a reduction in release of skeletal Ca2+. GRPC6A (GPCR, class C, group 6, subtype A) is a widely expressed amino acid-sensing GPCR that is most closely related to CaSR. GPRC6A is most potently activated by the basic amino acids L-arginine, L-lysine, and L-ornithine and less potently by small aliphatic amino acids. Moreover, the receptor can be either activated or modulated by divalent cations such as Ca2+. GPRC6A is expressed in the testis, but not the ovary and specifically also binds to the osteoblast-derived hormone osteocalcin (OCN), which regulates testosterone production by the testis and male fertility independently of the hypothalamic-pituitary axis. Furthermore, GPRC6A knockout studies suggest that GRPC6A is involved in regulation of bone metabolism, male reproduction, energy homeostasis, glucose metabolism, and in activation of inflammation response, as well as prostate cancer growth and progression, among others.