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|Title:||Glu(106) in the Orai1 pore contributes to fast Ca(2+)-dependent inactivation and pH dependence of Ca(2+) release-activated Ca(2+) (CRAC) current|
|Citation:||Biochemical Journal, 2012; 441(2):743-753|
|Nathan R. Scrimgeour, David P. Wilson and Grigori Y. Rychkov|
|Abstract:||FCDI (fast Ca2+ -dependent inactivation) is a mechanism that limits Ca2+ entry through Ca2+ channels, including CRAC (Ca2+release-activated Ca2+ ) channels. This phenomenon occurs when the Ca2+ concentration rises beyond a certain level in the vicinity of the intracellular mouth of the channel pore. In CRAC channels, several regions of the pore-forming protein Orai1, and STIM1 (stromal interaction molecule 1), the sarcoplasmic/endoplasmic reticulum Ca2+ sensor that communicates the Ca2+ load of the intracellular stores to Orai1, have been shown to regulate fast Ca2+ -dependent inactivation. Although significant advances in unravelling the mechanisms of CRAC channel gating have occurred, the mechanisms regulating fast Ca2+ -dependent inactivation in this channel are not well understood. We have identified that a poremutation, E106D Orai1, changes the kinetics and voltage dependence of the ICRAC (CRAC current), and the selectivity of the Ca2+ -binding site that regulates fast Ca2+ - dependent inactivation, whereas the V102I and E190Q mutants when expressed at appropriate ratios with STIM1 have fast Ca2+ -dependent inactivation similar to that of WT (wild-type) Orai1. Unexpectedly, the E106D mutation also changes the pH dependence of ICRAC.UnlikeWTICRAC, E106D-mediated current is not inhibited at low pH, but instead the block of Na+ permeation through the E106D Orai1 pore by Ca2+ is diminished. These results suggest that Glu106 inside the CRAC channel pore is involved in co-ordinating the Ca2+ -binding site that mediates fast Ca2+ -dependent inactivation.|
|Keywords:||calcium; Ca2+ release-activated Ca2+ current (ICRAC); gating; patch clamp; pH dependence|
|Rights:||© The Authors|
|Appears in Collections:||Physiology publications|
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