Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels
Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels
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DOI：
10.1073/pnas.0904664106
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发表时间：
2009-08-25
影响因子：
11.1
通讯作者：
Muallem, Shmuel
中科院分区：
文献类型：
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作者：
Lee, Kyu Pil;Yuan, Joseph P.;Muallem, Shmuel
钙池操纵的钙内流通道（SOC）介导的钙内流可介导多种受钙调节的细胞功能，SOC介导的钙内流具有细胞毒性并与疾病相关。SOC的一种形式是由STIM 1激活的奥赖通道介导的CRAC电流。天然CRAC和Orais的基本性质是快速Ca 2+依赖性失活，其限制Ca 2+内流以防止细胞损伤。这种重要调控机制的分子机制尚不清楚。我们在这里报告的快速Ca 2+依赖性失活是由三个保守的谷氨酸在C末端（CT）的Orai 2和Orai 3，这显示出突出的快速Ca 2+依赖性失活相比，Orai 1。CT在Orais之间的转移转移了通道开放的程度和快速Ca 2+依赖性失活的模式。Orai的快速Ca 2+依赖性失活也需要STIM 1的结构域;有效打开奥赖通道的STIM 1片段不会引起快速失活，除非它们包含STIM 1-奥赖激活区（SOAR）C末端的阴离子序列。我们的研究表明，奥赖CT是必要的和足够的控制孔开放，并揭示了快速钙依赖性失活的分子机制，具有影响的生理和病理状态下的钙内流SOC。
Ca2+ influx by store-operated Ca2+ influx channels (SOCs) mediates many cellular functions regulated by Ca2+, and excessive SOC-mediated Ca2+ 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 Ca2+-dependent inactivation, which limits Ca2+ influx to guard against cellular damage. The molecular mechanism of this essential regulatory mechanism is unknown. We report here the fast Ca2+-dependent inactivation is mediated by three conserved glutamates in the C termini (CT) of Orai2 and Orai3, which show prominent fast Ca2+-dependent inactivation compared with Orai1. Transfer of the CT between the Orais transfers both the extent of channel opening and the mode of fast Ca2+-dependent inactivation. Fast Ca2+-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 Ca2+-dependent inactivation that has implications for Ca2+ influx by SOC in physiological and pathological states.