Store-operated calcium channels

In electrically nonexcitable cells, Ca2+ 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 Ca2+ entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca2+ stores activates Ca2+ influx (store-operated Ca2+ entry, or capacitative Ca2+ entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the Ca2+ release-activated Ca2+ 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 Ca2+ content to CRAC channels in the plasma membrane, as well as the molecular identity of the Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ entry pathway.