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Ca²⁺ entry into cells of the peripheral immune system occurs through highly Ca²⁺-selective channels known as CRAC (calcium release-activated calcium) channels. CRAC channels are a very well-characterized example of store-operated Ca²⁺ channels, so designated because they open when the endoplasmic reticulum (ER) Ca²⁺ store becomes depleted. Physiologically, Ca²⁺ is released from the ER lumen into the cytoplasm when activated receptors couple to phospholipase C and trigger production of the second messenger inositol 1,4,5-trisphosphate (IP₃). IP₃ binds to IP₃ receptors in the ER membrane and activates Ca²⁺ release. The proteins STIM and ORAI were discovered through limited and genome-wide RNAi screens, respectively, performed in Drosophila cells and focused on identifying modulators of store-operated Ca²⁺ entry. STIM1 and STIM2 sense the depletion of ER Ca²⁺ stores, whereas …