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, Leigh Quarles

Research output: Contribution to journalArticle

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Abstract

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 β-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Gαq-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6 A 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.

Original languageEnglish (US)
Pages (from-to)40201-40209
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number48
DOIs
StatePublished - Dec 2 2005

Fingerprint

Calcium-Sensing Receptors
G-Protein-Coupled Receptors
Cations
Calcium
Bone
Osteocalcin
Osteoblasts
Bone and Bones
N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
Chemical activation
Arrestins
GTP-Binding Protein Regulators
Tissue
Amino Acids
Strontium
Calcium-Binding Proteins
Pertussis Toxin
Gadolinium
Transcription
Aluminum

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Identification of a novel extracellular cation-sensing G-protein-coupled receptor. / Pi, Min; Faber, Pieter; Ekema, George; Jackson, P. David; Ting, Anthony; Wang, Nancy; Fontilla-Poole, Michelle; Mays, Robert W.; Brunden, Kurt R.; Harrington, John J.; Quarles, Leigh.

In: Journal of Biological Chemistry, Vol. 280, No. 48, 02.12.2005, p. 40201-40209.

Research output: Contribution to journalArticle

Pi, M, Faber, P, Ekema, G, Jackson, PD, Ting, A, Wang, N, Fontilla-Poole, M, Mays, RW, Brunden, KR, Harrington, JJ & Quarles, L 2005, 'Identification of a novel extracellular cation-sensing G-protein-coupled receptor', Journal of Biological Chemistry, vol. 280, no. 48, pp. 40201-40209. https://doi.org/10.1074/jbc.M505186200
Pi, Min ; Faber, Pieter ; Ekema, George ; Jackson, P. David ; Ting, Anthony ; Wang, Nancy ; Fontilla-Poole, Michelle ; Mays, Robert W. ; Brunden, Kurt R. ; Harrington, John J. ; Quarles, Leigh. / Identification of a novel extracellular cation-sensing G-protein-coupled receptor. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 48. pp. 40201-40209.
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AU - Fontilla-Poole, Michelle

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