Store-Operated Calcium Channels

Department of Physiology, University of Oxford, Oxford, United Kingdom; and National Institute of Environmental Health Sciences-NIH, Research Triangle Park, North Carolina 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.