GPRC6A is a widely-expressed class C G protein-coupled receptor activated by multiple ligands including basic amino acids (L-lysine, L-arginine, L-ornithine), divalent cations (Ca²⁺, Mg²⁺), osteocalcin, and testosterone 1. The receptor couples primarily through Gq/11 and Gi pathways 2 to regulate diverse physiological processes. A key endocrine function involves osteocalcin-GPRC6A signaling in Leydig cells, where uncarboxylated osteocalcin binding promotes testosterone synthesis through CREB-dependent mechanisms 3. In humans, the rs2247911 polymorphism associates with testosterone production and sperm count 3. GPRC6A integrates metabolic signals by coordinating hormone secretion (insulin, GLP-1, testosterone, IL-6) and regulating glucose and fat metabolism across liver, muscle, and adipose tissue 1. The human variant GPRC6A-KGKY, distinct from the ancestral GPRC6A-KGRKLP found in other species, exhibits intracellular retention yet remains functional through β-arrestin-dependent signaling and promotes mTORC1 activation and prostate cancer cell proliferation in response to testosterone 4. Loss of GPRC6A in mouse models results in metabolic syndrome, while activation protects against high-fat diet-induced metabolic abnormalities 1. GPRC6A expression increases in prostate cancer, and its inhibition attenuates disease progression 1. However, physiological functions remain incompletely understood in humans, with conflicting evidence from different knockout mouse models regarding glucose homeostasis and bone metabolism 2.