The GPCR, class C, group 6, subtype A (GPRC6A) receptor: from cloning to physiological function

Abstract

GPRC6A (GPCR, class C, group 6, subtype A) is a class C GPCR that has been cloned from human, mouse and rat. Several groups have shown that the receptor is activated by a range of basic and small aliphatic L-α-amino acids of which L-arginine, L-lysine and L-ornithine are the most potent compounds with EC50 values in the mid-micromolar range. In addition, several groups have shown that the receptor is either directly activated or positively modulated by divalent cations such as Ca 2+ albeit in concentrations above 5 mM, which is above the physiological concentration in most tissues. More recently, the peptide osteocalcin and the steroid testosterone have also been suggested to be endogenous GPRC6A agonists. The receptor is widely expressed in all three species which, along with the omnipresence of the amino acids and divalent cation ligands, suggest that the receptor could be involved in a broad range of physiological functions. So far, this has mainly been addressed by analyses of genetically modified mice where the GPRC6A receptor has been ablated. Although there has been some discrepancies among results reported from different groups, there is increasing evidence that the receptor is involved in regulation of inflammation, metabolism and endocrine functions. GPRC6A could thus be an interesting target for new drugs in these therapeutic areas. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

“…Quarles et al have shown that alternative calcium-sensing molecules are expressed in osteoblasts. Molecules such as the intracellular protein calcyclin [68] and a membrane G-protein-coupled receptor, GPRC6A, unrelated to the CaSR, can sense calcium (albeit in supraphysiological concentration above 5 mM) and other divalent cations, but also extracellular L-amino acids (mainly, Larginine and L-ornithine), osteocalcin and the steroid testosterone, as demonstrated in vitro [69][70][71]. In fact, mice devoid of GPRC6A (obtained by selective deletion of exon 2 encoding for a minor part of the extracellular domain) display a phenotype characterized by osteopenia, feminization, and metabolic syndrome, a phenotype which seems mostly due to the altered osteocalcin signaling [72,73].…”

“…In particular, these latter mice are viable, fertile, and normally developed and do not show any abnormality in bone mineral density and metabolism, suggesting that GPRC6A does not play a key role in normal bone physiology [75, reviewed in 72]. Although it has been hypothesized that the GPRC6A might dimerize or colocalize with the CaSR to some extent to exert downstream signals, further studies are necessary to dissect the roles of this widely expressed molecule [71].…”

Role of post-translational modifications on structure, function and pharmacology of class C G protein-coupled receptors

“…22 different GPCRs have been classified as belonging to the class C GPCRs: eight metabotropic glutamate (mGlu 1-8 ) receptors, two GABA B receptors (GABA B1 and GABA B2 ), three taste receptors (T1R1-3), one calcium-sensing (CaS) receptor, one GPCR, class C, group 6, subtype A (GPRC 6 ) receptor, and seven orphan receptors (GPR156, GPR158, GPR179, GPRC5A-D) (Clemmensen et al, 2014). Very little is known about the orphan class C receptors including their PTMs and they have thus not been included in the review.…”

Arginine-induced insulin secretion in endoplasmic reticulum

“…Oya et al (2013) reported that EC 50 to GPRC6A is Orn > Lys ¼ Arg [4]. Final example is Cysteine, it is one of the strongest affinity to GPRC6A [5], but inhibit insulin secretion in mice [6,7]. Insulin secretagogues activity and affinity to GPRC6A of amino acid are different.…”

“…L-amino acids (not only cationic, but also non-cationic), calcium, osteocalcin, steroids, and so on, are the ligands of GPRC6A. Some L-amino acids which do not stimulate insulin secretion [1], for example Cysteine binds to GPRC6A [5], but even Cysteine inhibits insulin secretion in mice [6,7]. Our purpose is to identify the molecular mechanism of arginine action on insulin secretion.…”