Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks

Abstract

Emerging evidence supports the hypothesis that the skeleton is an endocrine organ that regulates energy metabolism through the release of the osteoblast-derived hormone, osteocalcin (Ocn). This bone-pancreas endocrine network is controversial because important gaps remain to be filled in our knowledge of the physiological effects of Ocn in multiple organs and the complex alterations in other hormonal networks induced by Ocn administration. A key step toward understanding the integrative regulation of energy metabolism by bone is the identification of GPCR family C group 6 member A (GPRC6A) as the Ocn receptor. GPRC6A is an amino acid-sensing G protein-coupled receptor highly expressed in β-cells and is activated by recombinant Ocn in vitro and in vivo but that is widely expressed in tissues other than the pancreas and is capable of sensing multiple structurally unrelated ligands, including l-amino acids, cations, and anabolic steroids in addition to Ocn. The broad expression and multiligand specificity of GPRC6A is identifying both systemic and paracrine regulation of seemingly disparate biological processes, ranging from energy metabolism, sexual reproduction, hypothalamic-pituitary function, bone formation, and prostate cancer. Consistent with the existence of more complex endocrine networks, ablation of GPRC6A in Gprc6a(-/-) mice results in complex metabolic abnormalities, including obesity, glucose intolerance, hepatic steatosis, insulin resistance, hyperphosphatemia, osteopenia, plus several hormonal abnormalities, including decreased circulating testosterone, IGF-I, and insulin and increased estradiol, LH, GH, and leptin. Recombinant Ocn also regulates testosterone production by the testes and male fertility through a GPRC6A-dependent mechanism, and testosterone regulation of LH secretion is abnormal in Gprc6a(-/-) mice. Thus, GPRC6A, as the biologically relevant receptor for Ocn, defines not only a molecular mechanism for linking bone metabolism with metabolic regulation of β-cells and sexual reproduction but also as a receptor shared by testosterone and dietary factors, and it is also involved in multiple endocrine networks integrating the functions of pancreas, muscle, liver, fat, testes, bone, and the hypothalamic-pituitary axis with alterations in both environmental and endogenous ligands.

Fig. 1.

A, Ocn released from bone resorption activates GPRC6A to regulate insulin secretion in β-cells. Insulin stimulates bone resorption releasing bioactive Ocn. GPRC6A may also be a receptor shared by nutrients (B) and testosterone, which stimulates insulin secretion (C). In addition, Ocn may target GPRC6A in other tissues to regulate testosterone production (C) and to promote insulin sensitivity (D). GPRC6A ligands may also regulate LH production.

Fig. 2.

Hypothetical model of ligand activation and allosteric modulation of GPRC6A. GPRC6A consists of a VFTM for sensing nutrients and the 7-TM domain and like other members of this family may function as a dimer. The orthotopic agonists, such as L-Arg and Ca²⁺, which are likely to be the natural ligands, binding sites are located adjacent to each other in the VFTM, whereas binding sites for allosteric modulators, such as calcimimetics, are located in the 7-TM region, possibly representing a retained (cryptic) ligand binding site in the classical GPCR region. We hypothesize that Ocn and testosterone (T) are also allosteric activators of GPRC6A with mechanism of activation similar to calcimimetics because they require the presence of a threshold concentration of Ca²⁺ for signaling to occur. Other amino acids and cations activate GPRC6A (61).