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Publication : Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells.

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.
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