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J. Biol. Chem., Vol. 281, Issue 50, 38730-38737, December 15, 2006

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Requirement of the TRPC1 Cation Channel in the Generation of Transient Ca²⁺ Oscillations by the Calcium-sensing Receptor^*

Osvaldo Rey¹, Steven H. Young, Romeo Papazyan, Mark S. Shapiro², and Enrique Rozengurt³

From the Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095 and Department of Physiology, University of Texas Health Science Center, San Antonio, Texas 78229

The calcium-sensing receptor (CaR) is an allosteric protein that responds to extracellular Ca²⁺ ([Ca²⁺]_o) and aromatic amino acids with the production of different patterns of oscillations in intracellular Ca²⁺ concentration ([Ca²⁺]_i). An increase in [Ca²⁺]_o stimulates phospholipase C-mediated production of inositol 1,4,5-trisphosphate and causes sinusoidal oscillations in [Ca²⁺]_i. Conversely, aromatic amino acid-induced CaR activation does not stimulate phospholipase C but engages an unidentified signaling mechanism that promotes transient oscillations in [Ca²⁺]_i. We show here that the [Ca²⁺]_i oscillations stimulated by aromatic amino acids were selectively abolished by TRPC1 down-regulation using either a pool of small inhibitory RNAs (siRNAs) or two different individual siRNAs that targeted different coding regions of TRPC1. Furthermore, [Ca²⁺]_i oscillations stimulated by aromatic amino acids were also abolished by inhibition of TRPC1 function with an antibody that binds the pore region of the channel. We also show that aromatic amino acid-stimulated [Ca²⁺]_i oscillations can be prevented by protein kinase C (PKC) inhibitors or siRNA-mediated PKC down-regulation and impaired by either calmodulin antagonists or by the expression of a dominant-negative calmodulin mutant. We propose a model for the generation of CaR-mediated transient [Ca²⁺]_i oscillations that integrates its stimulation by aromatic amino acids with TRPC1 regulation by PKC and calmodulin.

Received for publication, June 21, 2006 , and in revised form, October 10, 2006.

^* This work was supported in part by National Institutes of Health Grants K01CA097956 (to O. R.) and DK 55003 and DK 56930 (to E. R.). 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.

² Supported by National Institutes of Health Grant RO1 NS043394.

³ The Ronald S. Hirshberg Professor of Translational Pancreatic Cancer Research.

¹ To whom correspondence should be addressed: 900 Veteran Ave., Warren Hall Rm. 11-147, Dept. of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1786. Tel.: 310-794-5902; Fax: 310-267-2399; E-mail: orey{at}mednet.ucla.edu.

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