Fig. 3. Schematic illustration of ORAI1 and STIM1 in forming CRAC channel and NFAT activation in response to increased intracellular Ca²⁺. STIM1, is a Ca²⁺ sensor that is bound to the endoplasmic reticulum (ER). Release of ER Ca²⁺ via InsP3R leads to dissociation of Ca²⁺ from the binding site of STIM1, which enables it to dissociate from the ER and migrates to the cell membrane where it binds to ORAI1 to activate CRAC channel and Ca²⁺ entry into cells. Sustained Ca²⁺ influx into cytosol via CRAC leads to the activation of Ca²⁺-dependent enzyme calcineurin via its binding to calmodulin (CaM) and NFAT dephosphorylation leading to its translocation into nucleus, initiating transcription and cytokine expression.