HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 44, 37013-37020, November 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/44/37013    most recent M506681200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ray, K. Articles by Northup, J. K. Search for Related Content PubMed PubMed Citation Articles by Ray, K. Articles by Northup, J. K. Social Bookmarking                      What's this?

Calindol, a Positive Allosteric Modulator of the Human Ca²⁺ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca^2+*

Kausik Ray1, Justin Tisdale, Robert H. Dodd, Philippe Dauban, Martial Ruat¶, and John K. Northup

From the Laboratory of Cellular Biology, NIDCD, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Institut de Neurobiologie Alfred Fessard, IFR 2118 CNRS and Signal Transduction and Developmental Neuropharmacology, CNRS UPR9040, and the Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, 91198 Gif-sur-Yvette, France

The extracellular calcium-sensing human Ca²⁺ receptor (hCaR),² a member of the family-3 G-protein-coupled receptors (GPCR) possesses a large amino-terminal extracellular ligand-binding domain (ECD) in addition to a seven-transmembrane helical domain (7TMD) characteristic of all GPCRs. Two calcimimetic allosteric modulators, NPS R-568 and Calindol ((R)-2-{1-(1-naphthyl)ethyl-aminom-ethyl}indole), that bind the 7TMD of the hCaR have been reported to potentiate Ca²⁺ activation without independently activating the wild type receptor. Because agonists activate rhodopsin-like family-1 GPCRs by binding within the 7TMD, we examined the ability of Calindol, a novel chemically distinct calcimimetic, to activate a Ca²⁺ receptor construct (T903-Rhoc) in which the ECD and carboxyl-terminal tail have been deleted to produce a rhodopsin-like 7TMD. Here we report that although Calindol has little or no agonist activity in the absence of extracellular Ca²⁺ for the ECD-containing wild type or carboxyl-terminal deleted receptors, it acts as a strong agonist of the T903-Rhoc. In addition, Ca²⁺ alone displays little or no agonist activity for the hCaR 7TMD, but potentiates the activation by Calindol. We confirm that activation of Ca²⁺ T903-Rhoc by Calindol truly the is independent using in vitro reconstitution with purified G_q. These findings demonstrate distinct allosteric linkages between Ca²⁺ site(s) in the ECD and 7TMD and the 7TMD site(s) for calcimimetics.

Received for publication, June 20, 2005 , and in revised form, August 31, 2005.

^* This work was supported in part by the Intramural Research Program of the National Institutes of Health, NIDCD. 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: 5 Research Ct., Rm. 2A11, Rockville, MD 20850. Tel.: 301-496-9168; E-mail: rayk{at}nidcd.nih.gov.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Binet, B. Duthey, J. Lecaillon, C. Vol, J. Quoyer, G. Labesse, J.-P. Pin, and L. Prezeau Common Structural Requirements for Heptahelical Domain Function in Class A and Class C G Protein-coupled Receptors J. Biol. Chem., April 20, 2007; 282(16): 12154 - 12163. [Abstract] [Full Text] [PDF]

				K. Ray, K. A. Adipietro, C. Chen, and J. K. Northup Elucidation of the Role of Peptide Linker in Calcium-sensing Receptor Activation Process J. Biol. Chem., February 23, 2007; 282(8): 5310 - 5317. [Abstract] [Full Text] [PDF]