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J. Biol. Chem., Vol. 280, Issue 48, 40201-40209, December 2, 2005

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Identification of a Novel Extracellular Cation-sensing G-protein-coupled Receptor^*

Min Pi, Pieter Faber, George Ekema, P. David Jackson, Anthony Ting, Nancy Wang, Michelle Fontilla-Poole, Robert W. Mays, Kurt R. Brunden, John J. Harrington, and L. Darryl Quarles1

From the Kidney Institute, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160 and Athersys, Inc., Cleveland, Ohio 44115

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of -arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative G_q-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.

Received for publication, May 11, 2005 , and in revised form, August 19, 2005.

^* The work was supported by NIAMS, National Institutes of Health Grant 2R01AR037308. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Kidney Institute and Division of Nephrology, 3901 Rainbow Boulevard, 6018 Wahl Hall East, Kansas City, KS 66160. Tel.: 913-588-9255; Fax: 913-5889251; E-mail: dquarles{at}kumc.edu.

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