Parekh Anant B, Putney James W
Department of Physiology, University of Oxford, United Kingdom.
Physiol Rev. 2005 Apr;85(2):757-810. doi: 10.1152/physrev.00057.2003.
In electrically nonexcitable cells, Ca(2+) influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. The major Ca(2+) entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca(2+) stores activates Ca(2+) influx (store-operated Ca(2+) entry, or capacitative Ca(2+) entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca(2+) release-activated Ca(2+) current, I(CRAC). Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for I(CRAC)-like currents in excitable cells too. In spite of intense research, the signal that relays the store Ca(2+) content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca(2+) sensor within the stores, remains elusive. Resolution of these issues would be greatly helped by the identification of the CRAC channel gene. In some systems, evidence suggests that store-operated channels might be related to TRP homologs, although no consensus has yet been reached. Better understood are mechanisms that inactivate store-operated entry and hence control the overall duration of Ca(2+) entry. Recent work has revealed a central role for mitochondria in the regulation of I(CRAC), and this is particularly prominent under physiological conditions. I(CRAC) therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of I(CRAC) and other store-operated Ca(2+) currents and how they are regulated, and we consider recent advances that have shed insight into the molecular mechanisms involved in this ubiquitous and vital Ca(2+) entry pathway.
在电非兴奋性细胞中，Ca(2+)内流对于调节一系列动力学上不同的过程至关重要，这些过程包括胞吐作用、酶控制、基因调控、细胞生长与增殖以及细胞凋亡。这些细胞中主要的Ca(2+)进入途径是储存-操纵性途径，其中细胞内Ca(2+)储存的排空会激活Ca(2+)内流（储存-操纵性Ca(2+)进入，或容量性Ca(2+)进入）。已经报道了几种生物物理特性不同的储存-操纵性电流，但特征最明显的是Ca(2+)释放激活的Ca(2+)电流，即I(CRAC)。尽管它最初被认为仅在非兴奋性细胞中起作用，但现在越来越多的证据表明，类似I(CRAC)的电流在兴奋性细胞中也起着核心作用。尽管进行了深入研究，但将储存Ca(2+)含量传递到质膜中CRAC通道的信号以及储存内Ca(2+)传感器的分子身份仍然难以捉摸。鉴定CRAC通道基因将极大地有助于解决这些问题。在一些系统中，有证据表明储存-操纵性通道可能与TRP同源物有关，尽管尚未达成共识。对于使储存-操纵性进入失活从而控制Ca(2+)进入总持续时间的机制，人们有了更好的理解。最近的研究揭示了线粒体在I(CRAC)调节中的核心作用，并且在生理条件下这一作用尤为突出。因此，I(CRAC)代表了内质网、线粒体和质膜之间的动态相互作用。在这篇综述中，我们描述了I(CRAC)和其他储存-操纵性Ca(2+)电流的关键电生理特征以及它们是如何被调节的，并且我们考虑了最近的进展，这些进展使人们对这个普遍存在且至关重要的Ca(2+)进入途径所涉及的分子机制有了深入了解。
