Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Channels (Austin). 2011 Sep-Oct;5(5):424-31. doi: 10.4161/chan.5.5.16471. Epub 2011 Sep 1.
A rise in cytoplasmic [Ca2+] due to store-operated Ca2+ entry (SOCE) triggers a plethora of responses, both acute and long term. This leads to the important question of how this initial signal is decoded to regulate specific cellular functions. It is now clearly established that local [Ca2+] at the site of SOCE can vary significantly from the global [Ca2+] in the cytosol. Such Ca2+ microdomains are generated by the assembly of key Ca2+ signaling proteins within the domains. For example, GPCR, IP 3 receptors, TRPC3 channels, the plasma membrane Ca2+ pump and the endoplasmic reticulum (ER) Ca2+ pump have all been found to be assembled in a complex and all of them contribute to the Ca2+ signal. Recent studies have revealed that two other critical components of SOCE, STIM1 and Orai1, are also recruited to these regions. Thus, the entire machinery for activation and regulation of SOCE is compartmentalized in specific cellular domains which facilitates the specificity and rate of protein-protein interactions that are required for activation of the channels. In the case of TRPC1-SOC channels, it appears that specific lipid domains, lipid raft domains (LRDs), in the plasma membrane, as well as cholesterol-binding scaffolding proteins such as caveolin-1 (Cav-1), are involved in assembly of the TRPC channel complexes. Thus, plasma membrane proteins and lipid domains as well as ER proteins contribute to the SOCE-Ca2+ signaling microdomain and modulation of the Ca2+ signals per se. Of further interest is that modulation of Ca2+ signals, i.e. amplitude and/or frequency, can result in regulation of specific cellular functions. The emerging data reveal a dynamic Ca2+ signaling complex composed of TRPC1/Orai1/STIM1 that is physiologically consistent with the dynamic nature of the Ca2+ signal that is generated. This review will focus on the recent studies which demonstrate critical aspects of the TRPC1 channelosome that are involved in the regulation of TRPC1 function and TRPC1-SOC-generated Ca2+ signals.
细胞质内钙离子浓度的升高（Ca2+）由于钙库操纵性钙内流（SOCE）触发了许多急性和长期的反应。这就引出了一个重要的问题，即如何解码这个初始信号来调节特定的细胞功能。现在已经清楚地表明，SOCE 部位的局部 [Ca2+] 与细胞质中的整体 [Ca2+] 有很大的不同。这种 Ca2+ 微区是通过在该区域内组装关键的 Ca2+ 信号蛋白而产生的。例如，GPCR、IP3 受体、TRPC3 通道、质膜 Ca2+泵和内质网（ER）Ca2+泵都被发现组装在一个复合物中，它们都有助于 Ca2+信号。最近的研究表明，SOCE 的另外两个关键组成部分，STIM1 和 Orai1，也被招募到这些区域。因此，SOCE 的激活和调节的整个机制都被分隔在特定的细胞区域中，这有利于激活通道所需的蛋白质-蛋白质相互作用的特异性和速率。在 TRPC1-SOC 通道的情况下，似乎特定的脂质区域，即质膜中的脂质筏（LRD），以及胆固醇结合支架蛋白，如 caveolin-1（Cav-1），都参与了 TRPC 通道复合物的组装。因此，质膜蛋白和脂质区域以及 ER 蛋白都有助于 SOCE-Ca2+信号微区和 Ca2+信号本身的调节。更有趣的是，Ca2+ 信号的调节，即幅度和/或频率，可以导致特定细胞功能的调节。新出现的数据揭示了一个由 TRPC1/Orai1/STIM1 组成的动态 Ca2+ 信号复合物，这与所产生的 Ca2+信号的动态性质在生理上是一致的。这篇综述将重点介绍最近的研究，这些研究表明了 TRPC1 通道体中涉及调节 TRPC1 功能和 TRPC1-SOC 产生的 Ca2+信号的关键方面。
