| First Author | Pi M | Year | 2016 |
| Journal | Endocrinology | Volume | 157 |
| Issue | 5 | Pages | 1866-80 |
| PubMed ID | 27007074 | Mgi Jnum | J:234869 |
| Mgi Id | MGI:5791028 | Doi | 10.1210/en.2015-2010 |
| Citation | Pi M, et al. (2016) Evidence for Osteocalcin Binding and Activation of GPRC6A in beta-Cells. Endocrinology 157(5):1866-80 |
| abstractText | The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic beta-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A. Consistent with the modeling, mutations in the computationally identified binding pocket of GPRC6A reduced Ocn and C-terminal hexapeptide activation of this receptor. In addition, selective deletion of Gprc6a in beta-cells (Gprc6a(beta)(-cell-cko)) by crossing Gprc6a(flox/flox) mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and beta-cell proliferation were reduced in Gprc6a(beta)(-cell-cko) compared with control mice. Gprc6a(beta)(-cell-cko) exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6a(beta)(-cell-cko) mice showed reduced insulin simulation index in response to Ocn. These data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating beta-cell proliferation and insulin secretion. |
