Store-Operated CRAC Channels

In many animal cells, store-operated Ca²⁺ release-activated Ca²⁺ (CRAC) channels are an essential route for Ca²⁺ entry controlling a wide range of fundamental cellular functions including gene expression, secretion and cell proliferation. In line with their critical role in regulating cellular Ca²⁺ signaling, CRAC channels are also involved in the etiology of several disease processes including a severe combined immunodeficiency syndrome. CRAC channels are distinguished by several unique biophysical and molecular features including exquisite Ca²⁺ selectivity, low unitary conductance, and store-operated gating, and are formed from the assembly of two essential molecules: the STIM proteins, which serve as the ER Ca²⁺ sensors, and the ORAI proteins, which form the channel pore. ER Ca²⁺ store depletion triggers interactions between the STIM sensors and ORAI channels driving their redistribution and accumulation into overlapping puncta at peripheral cellular sites to elicit localized elevations of [Ca²⁺]_i at clusters of CRAC channels. This chapter examines the molecular features of the STIM and ORAI proteins that regulate the operation of CRAC channels and highlights key physiological roles in select organ systems.