title: GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo.
abstract: A bone-pancreas endocrine loop has been identified recently that involves insulin secreted from β-cells in the pancreas stimulating insulin receptors in osteoblasts, leading to osteoblastic differentiation and increased secretion of osteocalcin (Ocn), a bone-derived hormone that regulates insulin secretion in β-cells. The identity of the Ocn-sensing receptor in β-cells is a missing component of this endocrine loop. The abnormalities in glucose homeostasis in Gprc6a null mice suggests that this pertussis toxin-sensitive G protein-coupled receptor is a candidate for mediating the effects of Ocn on insulin secretion in the pancreas. In support of this possibility, we found that transfection of non-Gprc6a-expressing HEK-293 cells with a full-length Gprc6a cDNA imparted a dose-dependent response to Ocn (5 to 60 ng/mL), as measured by PKD1 and ERK phosphorylation. In addition, Gprc6a is highly expressed in mouse pancreatic tissue and in the mouse TC-6 pancreatic β-cell line. Ocn also stimulated ERK activity in TC-6 pancreatic β-cells. Finally, intraperitoneal injection of Ocn stimulated ERK activity in the pancreas and increased serum insulin levels in wild-type mice, but these responses were markedly attenuated in Gprc6a(-/-) mice. These findings suggest that GPRC6A is a candidate for mediating the response to Ocn in the bone-pancreas endocrine loop regulating insulin signaling.
authors.affiliation: Musculoskeletal, Orthopedic and Dental Institute and Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. mpi@uthsc.edu
authors.forename: Min
authors.initials: M
authors.lastname: Pi
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wu
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D015675:Osteocalcin / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection
chemical_list: C515750:GPRC6A protein, mouse; D043562:Receptors, G-Protein-Coupled; D015675:Osteocalcin