Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells [electronic resource].
- Washington, D.C. : United States. Dept. of Energy, 2016. and Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
- Physical Description:
- pages 1,866-1,880 : digital, PDF file
- Additional Creators:
- Oak Ridge National Laboratory, United States. Department of Energy, and United States. Department of Energy. Office of Scientific and Technical Information
- Restrictions on Access:
- Free-to-read Unrestricted online access
- 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 β-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 β-cells (Gprc6a<sup>β-cell-cko</sup>) by crossing Gprc6a<sup>flox/flox</sup> mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and β-cell proliferation were reduced in Gprc6a<sup>β-cell-cko</sup> compared with control mice. Gprc6a<sup>β-cell-cko</sup> exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6a<sup>β-cell-cko</sup> mice showed reduced insulin simulation index in response to Ocn. Here, these data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.
- Published through SciTech Connect., 05/01/2016., "100969", Endocrinology 157 5 ISSN 0013-7227 AM, and Min Pi; Karan Kapoor; Ruisong Ye; Satoru Kenneth Nishimoto; Jeremy C. Smith; Jerome Baudry; Leigh Darryl Quarles.
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