Evidence for osteocalcin binding and activation of GPRC6A in β-cells

Min Pi, Karan Kapoor, Ruisong Ye, Satoru Nishimoto, Jeremy C. Smith, Jerome Baudry, Leigh Quarles

Research output: Contribution to journalArticle

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Abstract

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-cell-cko) by crossing Gprc6aflox/flox 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 β-cell-cko compared with control mice. Gprc6a β-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6a β-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 β-cell proliferation and insulin secretion.

Original languageEnglish (US)
Pages (from-to)1866-1880
Number of pages15
JournalEndocrinology
Volume157
Issue number5
DOIs
StatePublished - May 1 2016

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Osteocalcin
Insulin
G-Protein-Coupled Receptors
Islets of Langerhans
Cell Proliferation
Structural Models
Insulin Resistance
Weights and Measures
Glucose
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Evidence for osteocalcin binding and activation of GPRC6A in β-cells. / Pi, Min; Kapoor, Karan; Ye, Ruisong; Nishimoto, Satoru; Smith, Jeremy C.; Baudry, Jerome; Quarles, Leigh.

In: Endocrinology, Vol. 157, No. 5, 01.05.2016, p. 1866-1880.

Research output: Contribution to journalArticle

Pi, Min ; Kapoor, Karan ; Ye, Ruisong ; Nishimoto, Satoru ; Smith, Jeremy C. ; Baudry, Jerome ; Quarles, Leigh. / Evidence for osteocalcin binding and activation of GPRC6A in β-cells. In: Endocrinology. 2016 ; Vol. 157, No. 5. pp. 1866-1880.
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