Molecular regulation of the pore component of CRAC channels, Orai1

Store-operated Ca(2+) entry (SOCE) is a fundamental mechanism ubiquitously employed by cells to elevate intracellular Ca(2+) concentrations ([Ca(2+)]i). Increased intracellular Ca(2+) ions act as a second messenger that can stimulate a variety of downstream signaling pathways affecting proliferation, secretion, differentiation, and death of cells. In immune cells, immune receptor stimulation induces endoplasmic reticulum Ca(2+) store depletion that subsequently activates Ca(2+)-release-activated-Ca(2+) (CRAC) channels, a prototype of store-operated Ca(2+) (SOC) channels. Identification of Orai1 as the pore subunit of CRAC channels has provided the much-needed molecular tool to dissect the mechanism of activation and regulation of these channels. In this review, we discuss the recent advances in understanding the regulatory mechanisms and posttranslational modifications that regulate diverse aspects of CRAC channel function.