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

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 (Gprc6aβ-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 Gprc6aβ-cell-cko compared with control mice. Gprc6aβ-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6aβ-cell-cko 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.

Authors:
 [1];  [2];  [1];  [1];  [3];  [2];  [1]
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States)
  2. Univ. of Tennessee/Oak Ridge National Lab. Center for Molecular Biophysics, Oak Ridge, TN (United States)
  3. Univ. of Tennessee/Oak Ridge National Lab. Center for Molecular Biophysics, Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1376607
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Endocrinology
Additional Journal Information:
Journal Volume: 157; Journal Issue: 5; Journal ID: ISSN 0013-7227
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Pi, Min, Kapoor, Karan, Ye, Ruisong, Nishimoto, Satoru Kenneth, Smith, Jeremy C., Baudry, Jerome, and Quarles, Leigh Darryl. Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells. United States: N. p., 2016. Web. doi:10.1210/en.2015-2010.
Pi, Min, Kapoor, Karan, Ye, Ruisong, Nishimoto, Satoru Kenneth, Smith, Jeremy C., Baudry, Jerome, & Quarles, Leigh Darryl. Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells. United States. doi:10.1210/en.2015-2010.
Pi, Min, Kapoor, Karan, Ye, Ruisong, Nishimoto, Satoru Kenneth, Smith, Jeremy C., Baudry, Jerome, and Quarles, Leigh Darryl. Sun . "Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells". United States. doi:10.1210/en.2015-2010. https://www.osti.gov/servlets/purl/1376607.
@article{osti_1376607,
title = {Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells},
author = {Pi, Min and Kapoor, Karan and Ye, Ruisong and Nishimoto, Satoru Kenneth and Smith, Jeremy C. and Baudry, Jerome and Quarles, Leigh Darryl},
abstractNote = {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 (Gprc6aβ-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 Gprc6aβ-cell-cko compared with control mice. Gprc6aβ-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6aβ-cell-cko 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.},
doi = {10.1210/en.2015-2010},
journal = {Endocrinology},
number = 5,
volume = 157,
place = {United States},
year = {2016},
month = {5}
}

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Works referencing / citing this record:

Human GPRC6A Mediates Testosterone-Induced Mitogen-Activated Protein Kinases and mTORC1 Signaling in Prostate Cancer Cells
journal, March 2019

  • Ye, Ruisong; Pi, Min; Nooh, Mohammed M.
  • Molecular Pharmacology, Vol. 95, Issue 5
  • DOI: 10.1124/mol.118.115014

Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease
journal, October 2018

  • Tacey, Alexander; Qaradakhi, Tawar; Brennan-Speranza, Tara
  • Nutrients, Vol. 10, Issue 10
  • DOI: 10.3390/nu10101426