Ambudkar Indu S, de Souza Lorena Brito, Ong Hwei Ling
Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Calcium. 2017 May;63:33-39. doi: 10.1016/j.ceca.2016.12.009. Epub 2016 Dec 30.
Store-operated calcium entry (SOCE) is a ubiquitous Ca entry pathway that is activated in response to depletion of ER-Ca 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 I, the highly Ca-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-Ca 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 I. 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 Ca 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 Ca 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 [Ca] signals. Thus, TRPC1 is activated downstream of Orai1 and modifies the initial [Ca] 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.
储存性钙内流（SOCE）是一种普遍存在的钙内流途径，它在细胞内质网（ER）钙库耗竭时被激活，并对多种细胞类型的生理功能调节起着关键作用。瞬时受体电位阳离子通道蛋白1（TRPC1）是TRPC通道亚家族中首个被鉴定为SOCE分子成分的成员。虽然TRPC1已被证明在许多细胞中对SOCE有贡献并调节多种功能，但报道的TRPC1介导的电流均与I电流不同，I电流是最早在淋巴细胞和肥大细胞中发现的高度钙选择性的储存依赖性电流。在TRPC1克隆近十年后，两种蛋白质被鉴定为钙释放激活钙通道（CRAC通道）的主要成分。第一种是基质相互作用分子1（STIM1），它是一种参与激活SOCE的内质网钙传感器蛋白。第二种是Orai1，它是CRAC通道的孔形成成分。STIM1和Orai1共表达可产生强大的I电流。重要的是，STIM1还通过其C末端多碱性结构域激活TRPC1，该结构域与其激活Orai1的结构域SOAR不同。此外，TRPC1的功能严重依赖于Orai1介导的钙内流，后者触发TRPC1募集到质膜中，然后在质膜中被STIM1激活。TRPC1和Orai1形成离散的STIM1门控通道，产生不同的钙信号并调节特定的细胞功能。TRPC1的表面表达可通过通道在质膜的进出运输进行调节，从而导致TRPC1介导的电流表型和[Ca]信号发生变化。因此，TRPC1在Orai1下游被激活，并在储存耗竭后改变由Orai1产生的初始[Ca]信号。本综述将总结当前关于TRPC1激活和调节概念的重要发现，以及其对细胞功能的影响。
