Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI

Ca 2+ entry into cells of the peripheral immune system occurs through highly Ca 2+ -selective channels known as CRAC (calcium release-activated calcium) channels. CRAC channels are a very well-characterized example of store-operated Ca 2+ channels, so designated because they open when the endoplasmic reticulum (ER) Ca 2+ store becomes depleted. Physiologically, Ca 2+ 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 (IP 3 ). IP 3 binds to IP 3 receptors in the ER membrane and activates Ca 2+ 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 Ca 2+ entry. STIM1 and STIM2 sense the depletion of ER Ca 2+ stores, whereas ORAI1 is a pore subunit of the CRAC channel. In this review, we discuss selected aspects of Ca 2+ signaling in cells of the immune system, focusing on the roles of STIM and ORAI proteins in store-operated Ca 2+ entry.