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J. Biol. Chem., Vol. 283, Issue 25, 17662-17671, June 20, 2008

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Store-dependent and -independent Modes Regulating Ca²⁺ Release-activated Ca²⁺ Channel Activity of Human Orai1 and Orai3^*

From the Department of Physiology and Biophysics, University of California, Irvine, California 92697

We evaluated currents induced by expression of human homologs of Orai together with STIM1 in human embryonic kidney cells. When co-expressed with STIM1, Orai1 induced a large inwardly rectifying Ca²⁺-selective current with Ca²⁺-induced slow inactivation. A point mutation of Orai1 (E106D) altered the ion selectivity of the induced Ca²⁺ release-activated Ca²⁺ (CRAC)-like current while retaining an inwardly rectifying I-V characteristic. Expression of the C-terminal portion of STIM1 with Orai1 was sufficient to generate CRAC current without store depletion. 2-APB activated a large relatively nonselective current in STIM1 and Orai3 co-expressing cells. 2-APB also induced Ca²⁺ influx in Orai3-expressing cells without store depletion or co-expression of STIM1. The Orai3 current induced by 2-APB exhibited outward rectification and an inward component representing a mixed calcium and monovalent current. A pore mutant of Orai3 inhibited store-operated Ca²⁺ entry and did not carry significant current in response to either store depletion or addition of 2-APB. Analysis of a series of Orai1-3 chimeras revealed the structural determinant responsible for 2-APB-induced current within the sequence from the second to third transmembrane segment of Orai3. The Orai3 current induced by 2-APB may reflect a store-independent mode of CRAC channel activation that opens a relatively nonselective cation pore.

Received for publication, February 26, 2008 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by a National Institutes of Health grant (to M. D. C.). This work was also supported by a University of California, Irvine, faculty career development award (to J. A. K.) and by fellowships from The George E. Hewitt Foundation (to S. L. Z.) and the American Heart Association (to Y. Y.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S8.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Neuroscience, Cell Biology, and Physiology, Wright State University, Biological Sciences Bldg., Rm. 122, Dayton, OH 45435.

³ To whom correspondence should be addressed: 285 Irvine Hall, Dept. of Physiology and Biophysics, University of California, Irvine, CA 92697. Tel.: 949-824-7776; Fax: 949-824-3143; E-mail: mcahalan{at}uci.edu.

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