CRAC Channels and Ca2+-Dependent Gene Expression

Pharmacological and siRNA-based approaches reveal that CRAC channel–gated Ca²⁺ microdomains activate Syk and calcineurin through distinct signaling pathways. The mutation of the conserved acidic residue E106 in transmembrane domain reduced Ca²⁺ influx and changed ion selectivity, establishing Orai1 as the pore-forming subunit of the CRAC channel. One conserved mechanism that links events at the cell surface to gene expression in the nucleus employs intracellular Ca²⁺. In neurons, Ca²⁺ entry through voltage-gated Ca²⁺ channels activates Ca²⁺-calmodulin-dependent protein kinases, leading to the phosphorylation of the transcription factor cAMP response-element binding protein. Although Ca²⁺ entry through CRAC channels is important in activating NFAT and c-fos, several lines of evidence show that Ca²⁺ microdomains near the mouth of open channels are more effective in activating the transcription factors than a rise in bulk cytoplasmic Ca²⁺. NFAT activation is mediated through the Ca²⁺-dependent stimulation of protein phosphatase 2B, the target of immunosuppressants cyclosporine A and tacrolimus.