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.

Calcium influx in nonexcitable cells regulates such diverse processes as exocytosis, contraction, enzyme control, gene regulation, cell proliferation, and apoptosis. The dominant Ca2+ entry pathway in these cells is the store-operated one, in which Ca2+ entry is governed by the Ca2+ content of the agonist-sensitive intracellular Ca2+ stores. Only recently has a Ca2+ current been described that is activated by store depletion. The properties of this new current, called Ca2+ release-activated Ca2+ current (ICRAC), have been investigated in detail using the patch-clamp technique. Despite intense research, the nature of the signal that couples Ca2+ store content to the Ca2+ channels in the plasma membrane has remained elusive. Although ICRAC appears to be the most effective and widespread influx pathway, other store-operated currents have also been observed. Although the Ca2+ release-activated Ca2+ channel has not yet been cloned, evidence continues to accumulate that the Drosophila trp gene might encode a store-operated Ca2+ channel. In this review, we describe the historical development of the field of Ca2+ signaling and the discovery of store-operated Ca2+ currents. We focus on the electrophysiological properties of the prototype store-operated current ICRAC, discuss the regulatory mechanisms that control it, and finally consider recent advances toward the identification of molecular mechanisms involved in this ubiquitous and important Ca2+ entry pathway.

Elevation of cytosolic Ca(2+) levels through the activation of store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels is involved in mediating a disparate array of cellular responses. These include secretion, metabolism and gene expression, as well as cell growth and proliferation. Moreover, emerging evidence points to the involvement of aberrant CRAC channel activity in human diseases, such as certain types of immunodeficiency and autoimmunity disorders, allergy, and inflammatory bowel disease. This article summarizes recent advances in understanding the gating and function of CRAC channels, their links to human disease and key issues for the development of channel blockers.

Patch-clamp experiments aimed at determining the relationship between intracellular Ca2+ release and activation of store-operated calcium current I(CRAC) reveal that both agonist and InsP3-mediated activation of I(CRAC) are highly nonlinear, occurring over a narrow concentration range. Ca2+ release and Ca2+ influx can be dissociated, as they possess differential sensitivities to InsP3: low concentrations induce substantial Ca2+ release without any activation of I(CRAC), whereas micromolar concentrations of InsP3 are required to activate Ca2+ influx. This suggests functionally distinct stores controlling Ca2+ release and influx and enables cells to switch between sources of Ca2+ to fit best their current needs.

In eukaryotic cells, hormones and neurotransmitters that engage the phosphoinositide pathway evoke a biphasic increase in intracellular free Ca 2+ concentration: an initial transient release of Ca 2+ from intracellular stores is followed by a sustained phase of Ca 2+ in¯ux. This in¯ux is generally store dependent. Most attention has focused on the link between the endoplasmic reticulum and store-operated Ca 2+ channels in the plasma membrane. Here, we describe that respiring mitochondria are also essential for the activation of macroscopic store-operated Ca 2+ currents under physiological conditions of weak intracellular Ca 2+ buffering. We further show that Ca 2+ -dependent slow inactivation of Ca 2+ in¯ux, a widespread but poorly understood phenomenon, is regulated by mitochondrial buffering of cytosolic Ca 2+ . Thus, by enabling macroscopic store-operated Ca 2+ current to activate, and then by controlling its extent and duration, mitochondria play a crucial role in all stages of store-operated Ca 2+ in¯ux. Store-operated Ca 2+ entry re¯ects a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.