Abstract
BackgroundGPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown.Methods/Principal FindingsIn this study, we created and characterized the phenotype of GPRC6A −/− mice. We observed complex metabolic abnormalities in GPRC6A −/− mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A −/− mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A −/− mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A−/− mice exhibited increments in urine Ca/Cr and PO4/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A −/− mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone.Conclusions/Significance GPRC6A−/− mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.
Highlights
GPRC6A is a recently identified member of family C of G protein-coupled receptors (GPCRs) that is most closely related to the calcium-sensing receptor CASR [1,2,3]
Wild-type GPRC6A+/+, heterozygous GPRC6A+/2, and homozygous GPRC6A2/2 mice were genotyped by PCR (Fig. 1B) and each genotype was found to be born at the expected Mendelian frequencies from heterozygous breeding pairs, breeding pairs consisting of GPRC6A2/26GPRC6A2/2 had litter sizes that were roughly half that of GPRC6A2/26GPRC6A+/+ or GPRC6A+/2 and GPRC6A+/2 breeding pairs, respectively (Data not shown)
We observed a complex phenotype in GPRC6A2/2 mice consisting of defective mineralization of bone and impaired osteoblast function in male and female mice, a decrease in lean body mass, an increase in fat mass, hyperphosphatemia and hypercalciuria, hyperglycemia and feminization of male mice associated with altered ratio of estradiol and testosterone, suggesting that GPRC6A participates in hormonal control of energy metabolism
Summary
GPRC6A is a recently identified member of family C of G protein-coupled receptors (GPCRs) that is most closely related to the calcium-sensing receptor CASR [1,2,3]. GPRC6A has recently been shown to sense extracellular cations and amino acids and to require both extracellular cations and amino acids for optimal stimulation in vitro [3]. This dual sensitivity of GPRC6A to both divalent cations and amino acids is analogous to the related receptor CASR [7]. GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro.
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