Orai1-and Orai2-, but not Orai3-mediated I-CRAC regulated by intracellular pH
The Journal of physiology(2022)
摘要
Three Orai (Orai1, Orai2, and Orai3) and two stromal interaction molecule (STIM1 and STIM2) mammalian protein homologues constitute major components of the store-operated a Ca2+ entry mechanism. When co-expressed with STIM1, Orai1, Orai2 and Orai3 form highly selective Ca2+ channels with properties of Ca2+ release-activated Ca2+ (CRAG) channels. Despite the high level of homology between Orai proteins, CRAG channels formed by different Orai isoforms have distinctive properties, particularly with regards to Ca2+-dependent inactivation, inhibition/potentiation by 2-aminoethyl diphenylborinate and sensitivity to reactive oxygen species. This study characterises and compares the regulation of Grail, Orai2- and Orai3-mediated CRAC current (I-CRAC) by intracellular pH (pH(i)). Using whole-cell patch clamping of HEK293T cells heterologously expressing Orai and STIM1, we show that I-CRAC formed by each Oral homologue has a unique sensitivity to changes in pH(i). Grail-mediated I-CRAC exhibits a strong dependence on pH(i), of both current amplitude and the kinetics of Ca2+-dependent inactivation. In contrast, Orai2 amplitude, but not kinetics, depends on pH(i), whereas Orai3 shows no dependence on pH(i) at all. Investigation of different Orai1-Orai3 chimeras suggests that pH(i) dependence of Orail resides in both the N-terminus and intracellular loop 2, and may also involve pH-dependent interactions with STIM1.
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关键词
Ca2+-dependent inactivation, gating, I-CRAC, Orai3, pH, STIM1
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