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This Article Full Text Full Text (PDF) All Versions of this Article: 586/1/185    most recent jphysiol.2007.146258v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mignen, O. Articles by Shuttleworth, T. J. Search for Related Content PubMed PubMed Citation Articles by Mignen, O. Articles by Shuttleworth, T. J. Related Collections Cellular

¹ Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
² CNRS UMR 8078, Université Paris Sud, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France

Agonist-activated Ca²⁺ signals in non-excitable cells are profoundly influenced by calcium entry via both store-operated and store-independent conductances. Recent studies have demonstrated that STIM1 plays a key role in the activation of store-operated conductances including the Ca²⁺-release-activated Ca²⁺ (CRAC) channels, and that Orai1 comprises the pore-forming component of these channels. We recently demonstrated that STIM1 also regulates the activity of the store-independent, arachidonic acid-regulated Ca²⁺ (ARC) channels, but does so in a manner entirely distinct from its regulation of the CRAC channels. This shared ability to be regulated by STIM1, together with their similar biophysical properties, suggested that these two distinct conductances may be molecularly related. Here, we report that whilst the levels of Orai1 alone determine the magnitude of the CRAC channel currents, both Orai1 and the closely related Orai3 are critical for the corresponding currents through ARC channels. Thus, in cells stably expressing STIM1, overexpression of Orai1 increases both CRAC and ARC channel currents. Whilst similar overexpression of Orai3 alone has no effect, ARC channel currents are specifically increased by expression of Orai3 in cells stably expressing Orai1. Moreover, expression of a dominant-negative mutant Orai3, either alone or in cells expressing wild-type Orai1, profoundly and specifically reduces currents through the ARC channels without affecting those through the CRAC channels, and siRNA-mediated knockdown of either Orai1 or Orai3 markedly inhibits ARC channel currents. Importantly, our data also show that the precise effects observed critically depend on which of the three proteins necessary for effective ARC channel activity (STIM1, Orai1 and Orai3) are rate limiting under the specific conditions employed.

(Received 4 October 2007; accepted after revision 7 November 2007; first published online 8 November 2007)
Corresponding author T. J. Shuttleworth: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA. Email: trevor_shuttleworth{at}urmc.rochester.edu

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