Calcium signaling in lymphocytes

In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription. After the engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca2+ stores as a result of binding of inositol trisphosphate (IP3) to IP3 receptors, followed by 'store-operated' Ca2+ entry through plasma membrane Ca2+ channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca2+ entry through specialized Ca2+ release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca2+ increase. A recent breakthrough in our understanding of CRAC channel function is the identification of stromal interaction molecule (STIM) and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca2+ influx (the STIM/ORAI and calcineurin/NFAT pathways, respectively).