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Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels.
J Physiol. 2008 Jan 01; 586(1):185-95.JP

Abstract

Agonist-activated Ca(2+) 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 Ca(2+)-release-activated Ca(2+) (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 Ca(2+) (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.

Authors+Show Affiliations

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17991693

Citation

Mignen, Olivier, et al. "Both Orai1 and Orai3 Are Essential Components of the Arachidonate-regulated Ca2+-selective (ARC) Channels." The Journal of Physiology, vol. 586, no. 1, 2008, pp. 185-95.
Mignen O, Thompson JL, Shuttleworth TJ. Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. J Physiol. 2008;586(1):185-95.
Mignen, O., Thompson, J. L., & Shuttleworth, T. J. (2008). Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. The Journal of Physiology, 586(1), 185-95.
Mignen O, Thompson JL, Shuttleworth TJ. Both Orai1 and Orai3 Are Essential Components of the Arachidonate-regulated Ca2+-selective (ARC) Channels. J Physiol. 2008 Jan 1;586(1):185-95. PubMed PMID: 17991693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. AU - Mignen,Olivier, AU - Thompson,Jill L, AU - Shuttleworth,Trevor J, Y1 - 2007/11/08/ PY - 2007/11/10/pubmed PY - 2008/5/20/medline PY - 2007/11/10/entrez SP - 185 EP - 95 JF - The Journal of physiology JO - J Physiol VL - 586 IS - 1 N2 - Agonist-activated Ca(2+) 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 Ca(2+)-release-activated Ca(2+) (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 Ca(2+) (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. SN - 0022-3751 UR - https://www.unboundmedicine.com/medline/citation/17991693/Both_Orai1_and_Orai3_are_essential_components_of_the_arachidonate_regulated_Ca2+_selective__ARC__channels_ L2 - https://doi.org/10.1113/jphysiol.2007.146258 DB - PRIME DP - Unbound Medicine ER -