Store-Operated Calcium Channels

Abstract

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, ICRAC. Although it was initially considered to function only in nonexcitable cells, growing evidence now points towards a central role for ICRAC-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 ICRAC, and this is particularly prominent under physiological conditions. ICRACtherefore represents a dynamic interplay between endoplasmic reticulum, mitochondria, and plasma membrane. In this review, we describe the key electrophysiological features of ICRACand 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.