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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity
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Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity

机译：Ca2 +内流的全基因组RNAi筛选可识别调节Ca2 +释放激活的Ca2 +通道活性的基因

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摘要

Recent studies by our group and others demonstrated a required and conserved role of Stim in store-operated Ca2+ influx and Ca2+ release-activated Ca2+ (CRAC) channel activity. By using an unbiased genome-wide RNA interference screen in Drosophila S2 cells, we now identify 75 hits that strongly inhibited Ca2+ influx upon store emptying by thapsigargin. Among these hits are 11 predicted transmembrane proteins, including Stim, and one, olf186-F, that upon RNA interference-mediated knockdown exhibited a profound reduction of thapsigargin-evoked Ca2+ entry and CRAC current, and upon overexpression a 3-fold augmentation of CRAC current. CRAC currents were further increased to 8-fold higher than control and developed more rapidly when olf186-F was cotransfected with Stim. olf186-Fis a member of a highly conserved family of four-transmembrane spanning proteins with homologs from Caenorhabditis elegans to human. The endoplasmic reticulum (ER) Ca2+ pump sarco-/ER calcium ATPase (SERCA) and the single transmembrane-soluble N-ethylmaleimide-sensitive (NSF) attachment receptor (SNARE) protein Syntaxin5 also were required for CRAC channel activity, consistent with a signaling pathway in which Stim senses Ca2+ depletion within the ER, translocates to the plasma membrane, and interacts with olf186-F to trigger CRAC channel activity.
机译：我们小组和其他人最近的研究表明，Stim在存储操作的Ca2 +内流和Ca2 +释放激活的Ca2 +（CRAC）通道活性中起着必要的和保守的作用。通过在果蝇S2细胞中使用无偏见的全基因组RNA干扰筛查，我们现在鉴定出75种命中物，它们被thapsigargin清空后强烈抑制了Ca2 +的流入。在这些命中物中，有11种预测的跨膜蛋白，包括Stim，一种是olf186-F，它们在RNA干扰介导的敲低后表现出毒胡萝卜素诱发的Ca2 +进入和CRAC电流的显着减少，而过表达则使CRAC增加3倍当前。当olf186-F与Stim共转染时，CRAC电流进一步增加到比对照高8倍，并且发展更快。 olf186-Fis是高度保守的四跨膜蛋白家族成员，其同源性从秀丽隐杆线虫到人类。 CRAC通道活性也需要内质网（ER）Ca2 +泵的sarco- / ER钙ATPase（SERCA）和单个跨膜可溶性N-乙基马来酰亚胺敏感（NSF）附着受体（SNARE）蛋白Syntaxin5，与信号传导一致Stim感应ER中Ca2 +耗尽，转运到质膜并与olf186-F相互作用以触发CRAC通道活性的途径。

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