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标题：Identification of key amino acid residues responsible for internal and external pH sensitivity of Orai1/STIM1 channels
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作者：Hiroto Tsujikawa ; Albert S Yu ; Jia Xie 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：5
DOI：10.1038/srep16747
出版社：Springer Nature
摘要：Changes of intracellular and extracellular pH are involved in a variety of physiological and pathological processes, in which regulation of the Ca²⁺ release activated Ca²⁺ channel (I_CRAC) by pH has been implicated. Ca²⁺ entry mediated by I_CRAC has been shown to be regulated by acidic or alkaline pH. Whereas several amino acid residues have been shown to contribute to extracellular pH (pH_o) sensitivity, the molecular mechanism for intracellular pH (pH_i) sensitivity of Orai1/STIM1 is not fully understood. By investigating a series of mutations, we find that the previously identified residue E106 is responsible for pH_o sensitivity when Ca²⁺ is the charge carrier. Unexpectedly, we identify that the residue E190 is responsible for pH_o sensitivity when Na⁺ is the charge carrier. Furthermore, the intracellular mutant H155F markedly diminishes the response to acidic and alkaline pH_i, suggesting that H155 is responsible for pH_i sensitivity of Orai1/STIM1. Our results indicate that, whereas H155 is the intracellular pH sensor of Orai1/STIM1, the molecular mechanism of external pH sensitivity varies depending on the permeant cations. As changes of pH are involved in various physiological/pathological functions, Orai/STIM channels may be an important mediator for various physiological and pathological processes associated with acidosis and alkalinization.