Photochemical gating of intracellular Ca2+ release channels.
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ABSTRACT:
SUBMITTER: Ni J
PROVIDER: S-EPMC2536572 | biostudies-literature | 2007 May
REPOSITORIES: biostudies-literature
Publications
Photochemical gating of intracellular Ca2+ release channels.
Ni Jiahong J Auston Darryl A DA Freilich David A DA Muralidharan Sukumaran S Sobie Eric A EA Kao Joseph P Y JP
Journal of the American Chemical Society 20070411 17
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Project description:Ca(2+) influx by store-operated Ca(2+) influx channels (SOCs) mediates many cellular functions regulated by Ca(2+), and excessive SOC-mediated Ca(2+) influx is cytotoxic and associated with disease. One form of SOC is the CRAC current that is mediated by Orai channels activated by STIM1. A fundamental property of the native CRAC and of the Orais is fast Ca(2+)-dependent inactivation, which limits Ca(2+) influx to guard against cellular damage. The molecular mechanism of this essential regulatory mechanism is unknown. We report here the fast Ca(2+)-dependent inactivation is mediated by three conserved glutamates in the C termini (CT) of Orai2 and Orai3, which show prominent fast Ca(2+)-dependent inactivation compared with Orai1. Transfer of the CT between the Orais transfers both the extent of channel opening and the mode of fast Ca(2+)-dependent inactivation. Fast Ca(2+)-dependent inactivation of the Orais also requires a domain of STIM1; fragments of STIM1 that efficiently open Orai channels do not evoke fast inactivation unless they include an anionic sequence that is C-terminal to the STIM1-Orai activating region (SOAR). Our studies suggest that Orai CT are necessary and sufficient to control pore opening and uncover the molecular mechanism of fast Ca(2+)-dependent inactivation that has implications for Ca(2+) influx by SOC in physiological and pathological states.
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