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J. Biol. Chem., Vol. 279, Issue 20, 21511-21519, May 14, 2004

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Subpopulation of Store-operated Ca²⁺ Channels Regulate Ca²⁺-induced Ca²⁺ Release in Non-excitable Cells^*

Jian Yao, Qin Li, Jin Chen, and Shmuel Muallem

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040

Ca²⁺-induced Ca²⁺ release (CICR) is a well characterized activity in skeletal and cardiac muscles mediated by the ryanodine receptors. The present study demonstrates CICR in the non-excitable parotid acinar cells, which resembles the mechanism described in cardiac myocytes. Partial depletion of internal Ca²⁺ stores leads to a minimal activation of Ca²⁺ influx. Ca²⁺ influx through this pathway results in an explosive mobilization of Ca²⁺ from the majority of the stores by CICR. Thus, stimulation of parotid acinar cells in Ca²⁺-free medium with 0.5 µM carbachol releases 5% of the Ca²⁺ mobilizable by 1 mM carbachol. Addition of external Ca²⁺ induced the same Ca²⁺ release observed in maximally stimulated cells. Similar results were obtained by a short treatment with 2.5-10 µM cyclopiazonic acid, an inhibitor of the sarco/endoplasmic reticulum Ca²⁺ ATPase pump. The Ca²⁺ release induced by the addition of external Ca²⁺ was largely independent of IP₃Rs because it was reduced by only 30% by the inhibition of the inositol 1,4,5-trisphosphate receptors with caffeine or heparin. Measurements of Ca²⁺-activated outward current and [Ca²⁺]_i suggested that most CICR triggered by Ca²⁺ influx occurred away from the plasma membrane. Measurement of the response to several concentrations of cyclopiazonic acid revealed that Ca²⁺ influx that regulates CICR is associated with a selective portion of the internal Ca²⁺ pool. The minimal activation of Ca²⁺ influx by partial store depletion was confirmed by the measurement of Mn²⁺ influx. Inhibition of Ca²⁺ influx with SKF96365or 2-aminoethoxydiphenyl borate prevented activation of CICR observed on addition of external Ca²⁺. These findings provide evidence for activation of CICR by Ca²⁺ influx in non-excitable cells, demonstrate a previously unrecognized role for Ca²⁺ influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca²⁺ influx is mediated by voltage-regulated Ca²⁺ channels whereas in non-excitable cells Ca²⁺ influx is mediated by store-operated channels.

Received for publication, December 22, 2003 , and in revised form, February 26, 2004.

^* This work was supported by National Institutes of Heath Grants DE12309 and DK38938 and Cystic Fibrosis Foundation Grant MUALLE01G0. 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.

To whom correspondence should be addressed: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-648-2593; Fax: 214-648-8879; E-mail: SHMUEL.MUALLEM{at}utsouthwestern.edu.

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