Journal
ENDOCRINOLOGY
Volume 157, Issue 5, Pages 1866-1880Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2015-2010
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Funding
- National Institutes of Health [R01-AR37308]
- Americans Diabetes Association [1-13-BS-149-BR]
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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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