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J. Biol. Chem., Vol. 280, Issue 24, 22875-22882, June 17, 2005

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Amino Acid-stimulated Ca²⁺ Oscillations Produced by the Ca²⁺-sensing Receptor Are Mediated by a Phospholipase C/Inositol 1,4,5-Trisphosphate-independent Pathway That Requires G₁₂, Rho, Filamin-A, and the Actin Cytoskeleton^*

Osvaldo Rey, Steven H. Young, Jingzhen Yuan, Lee Slice, and Enrique Rozengurt

From the Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, UCLA-CURE Digestive Diseases Research Center and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095

The G protein-coupled Ca²⁺-sensing receptor (CaR) is an allosteric protein that responds to two different agonists, Ca²⁺ and aromatic amino acids, with the production of sinusoidal or transient oscillations in intracellular Ca²⁺ concentration ([Ca²⁺]_i). Here, we examined whether these differing patterns of [Ca²⁺]_i oscillations produced by the CaR are mediated by separate signal transduction pathways. Using real time imaging of changes in phosphatidylinositol 4,5-biphosphate hydrolysis and generation of inositol 1,4,5-trisphosphate in single cells, we found that stimulation of CaR by an increase in the extracellular Ca²⁺ concentration ([Ca²⁺]_o) leads to periodic synthesis of inositol 1,4,5-trisphosphate, whereas L-phenylalanine stimulation of the CaR does not induce any detectable change in the level this second messenger. Furthermore, we identified a novel pathway that mediates transient [Ca²⁺]_i oscillations produced by the CaR in response to L-phenylalanine, which requires the organization of the actin cytoskeleton and involves the small GTPase Rho, heterotrimeric proteins of the G₁₂ subfamily, the C-terminal region of the CaR, and the scaffolding protein filamin-A. Our model envisages that Ca²⁺ or amino acids stabilize unique CaR conformations that favor coupling to different G proteins and subsequent activation of distinct downstream signaling pathways.

Received for publication, March 30, 2005

^* This work was supported in part by Grants DK 55003, DK 56930, 5 P30 DK41301, and NCI P50 CA090388 from the National Institute of Health (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.

Recipient of a NCI Mentored Career Development Award K01CA097956-03.

The Ronald S. Hirshberg Professor of Translational Pancreatic Cancer Research. To whom correspondence should be addressed: 900 Veteran Ave., Warren Hall Rm. 11-124, Dept. of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1786. Tel.: 310-794-6610; Fax: 310-267-2399; E-mail: erozengurt{at}mednet.ucla.edu.

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