proliferation, and apoptosis. Capacitative calcium entry appears to also be a major means of signal transduction. The major Ca2+ entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca2+ stores activates Ca2+ influx (store-operated Ca2+ entry, or capacitative Ca2+ entry). This is often referred to as the store-operated current or SOC. A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca2+ from intracellular stores (components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca2+ concentration within the lumen of the Ca2+-storing organelles subsequently activates plasma membrane Ca2+ channels. STIM Complex STIM1 is a Ca2+-sensor protein specialized for electrical signaling in the endoplasmic reticulum (ER). It interacts with and mediates store-dependent regulation of both Orai1 and TRPC1 channels. TRPC1+STIM1-dependent SOC requires functional Orai1. STIM1 is the mechanistic 'missing link' between the ER and the plasma membrane. STIM proteins sense the depletion of luminal Ca2+ from the ER and trigger activation of CRAC channels in the surface membrane after Ca2+ store depletion. The process involves oligomerization, then translocation to junctions adjacent to the plasma membrane, by which the CRAC channels become organized into clusters and then open to bring about SOC entry. Lymphocytes The primary mechanism of extracellular Ca2+ entry in lymphocytes involves CRAC channels. STIM1 is a crucial component of the CRAC influx mechanism in lymphocytes, acting as a sensor of low Ca2+ concentration in the ER and an activator of the Ca2+ selective channel ORAI1 in the plasma membrane. Yarkoni and Cambier (2011) reported that STIM1 expression differs in murine T and B lymphocytes; mature T cells express about 4 times more STIM1 than mature B cells. Through the physiologic range of expression, STIM1 levels determine the magnitude of Ca2+ influx responses that follow BCR-induced intracellular store depletion. SCID Antigen stimulation of immune cells triggers Ca2+ entry through tetrameric Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. Cells from patients with one form of hereditary Severe Combined Immune Deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. The genetic defect in these patients appears to be in ORAI1 (TM protein 142A; TMEM142a), which