Store-operated calcium entry (SOCE) is a ubiquitous Ca2+ entry pathway that is activated in response to depletion of ER-Ca2+ stores and critically controls the regulation of physiological functions in miscellaneous cell types. The transient receptor potential canonical 1 (TRPC1) is the first member of the TRPC channel subfamily to be identified as a molecular component of SOCE. While TRPC1 has been shown to contribute to SOCE and regulate various functions in many cells, none of the reported TRPC1-mediated currents resembled ICRAC, the highly Ca2+-selective store-dependent current first identified in lymphocytes and mast cells. Almost a decade after the cloning of TRPC1 two proteins were identified as the primary components of the CRAC channel. The first, STIM1, is an ER-Ca2+ sensor protein involved in activating SOCE. The second, Orai1 is the pore-forming component of the CRAC channel. Co-expression of STIM1 and Orai1 generated robust ICRAC. Importantly, STIM1 was shown to also activate TRPC1 via its C-terminal polybasic domain, which is distinct from its Orai1-activating domain, SOAR. In addition, TRPC1 function critically depends on Orai1-mediated Ca2+ entry which triggers recruitment of TRPC1 into the plasma membrane where it is then activated by STIM1. TRPC1 and Orai1 form discrete STIM1-gated channels that generate distinct Ca2+ signals and regulate specific cellular functions. Surface expression of TRPC1 can be modulated by trafficking of the channel to and from the plasma membrane, resulting in changes to the phenotype of TRPC1-mediated current and [Ca2+]i signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca2+]i signal generated by Orai1 following store depletion. This review will summarize the important findings that underlie the current concepts for activation and regulation of TRPC1, as well as its impact on cell function.

中文翻译：

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SOCE 中的 TRPC1、Orai1 和 STIM1：狭小空间中的朋友。

钙池操纵的钙内流 (SOCE) 是一种普遍存在的 Ca2+ 进入途径，它会随着 ER-Ca2+ 储备的耗尽而被激活，并严格控制各种细胞类型的生理功能的调节。瞬时受体电位规范 1 (TRPC1) 是 TRPC 通道亚家族中第一个被确定为 SOCE 分子成分的成员。虽然 TRPC1 已被证明有助于 SOCE 并调节许多细胞中的各种功能，但所报道的 TRPC1 介导的电流都与 ICRAC 相似，ICRAC 是首先在淋巴细胞和肥大细胞中发现的高度 Ca2+ 选择性储存依赖性电流。TRPC1 克隆近十年后，两种蛋白质被确定为 CRAC 通道的主要成分。第一个是 STIM1，是一种参与激活 SOCE 的 ER-Ca2+ 传感器蛋白。第二个，Orai1 是 CRAC 通道的成孔成分。STIM1 和 Orai1 的共表达产生了强大的 ICRAC。重要的是，STIM1 还可以通过其 C 端多元结构域激活 TRPC1，该结构域不同于其 Orai1 激活结构域 SOAR。此外，TRPC1 功能主要依赖于 Orai1 介导的 Ca2+ 进入，从而触发 TRPC1 募集到质膜中，然后被 STIM1 激活。TRPC1 和 Orai1 形成离散的 STIM1 门控通道，产生不同的 Ca2+ 信号并调节特定的细胞功能。TRPC1 的表面表达可以通过通道进出质膜的运输来调节，从而导致 TRPC1 介导的电流和 [Ca2+]i 信号的表型发生变化。因此，TRPC1 在 Orai1 下游被激活，并在储存耗尽后修改 Orai1 生成的初始 [Ca2+]i 信号。本综述将总结当前 TRPC1 激活和调节概念及其对细胞功能影响的重要发现。