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J. Biol. Chem., Vol. 283, Issue 18, 12512-12519, May 2, 2008

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Store-operated Ca²⁺ Influx Causes Ca²⁺ Release from the Intracellular Ca²⁺ Channels That Is Required for T Cell Activation^*

Sepehr Dadsetan, Liudmila Zakharova, Tadeusz F. Molinski, and Alla F. Fomina¹

From the Department of Physiology and Membrane Biology, University of California, Davis, Davis, California 95616 and Department of Chemistry and Biochemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093

The precise control of many T cell functions relies on cytosolic Ca²⁺ dynamics that is shaped by the Ca²⁺ release from the intracellular store and extracellular Ca²⁺ influx. The Ca²⁺ influx activated following T cell receptor (TCR)-mediated store depletion is considered to be a major mechanism for sustained elevation in cytosolic Ca²⁺ concentration ([Ca²⁺]_i) necessary for T cell activation, whereas the role of intracellular Ca²⁺ release channels is believed to be minor. We found, however, that in Jurkat T cells [Ca²⁺]_i elevation observed upon activation of the store-operated Ca²⁺ entry (SOCE) by passive store depletion with cyclopiazonic acid, a reversible blocker of sarco-endoplasmic reticulum Ca²⁺-ATPase, inversely correlated with store refilling. This indicated that intracellular Ca²⁺ release channels were activated in parallel with SOCE and contributed to global [Ca²⁺]_i elevation. Pretreating cells with (-)-xestospongin C (10 µM) or ryanodine (400 µM), the antagonists of inositol 1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR), respectively, facilitated store refilling and significantly reduced [Ca²⁺]_i elevation evoked by the passive store depletion or TCR ligation. Although the Ca²⁺ release from the IP3R can be activated by TCR stimulation, the Ca²⁺ release from the RyR was not inducible via TCR engagement and was exclusively activated by the SOCE. We also established that inhibition of IP3R or RyR down-regulated T cell proliferation and T-cell growth factor interleukin 2 production. These studies revealed a new aspect of [Ca²⁺]_i signaling in T cells, that is SOCE-dependent Ca²⁺ release via IP3R and/or RyR, and identified the IP3R and RyR as potential targets for manipulation of Ca²⁺-dependent functions of T lymphocytes.

Received for publication, November 13, 2007 , and in revised form, January 17, 2008.

^* This work was supported by American Heart Association Grant-in-aid 0755086Y (to A. F. F.) and by Philip Morris USA Inc. and Philip Morris International (to A. F. F.). 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: 4138 Tupper Hall, One Shields Ave., Davis, CA 95616. Tel.: 530-754-4454; E-mail: affomina{at}ucdavis.edu.

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