2013 Elsevier Inc. All rights reserved. Ca 2+ , a signal for life and death, is precisely yet flexibly controlled in cells to mediate diverse cellular processes. It has been recognized for more than two decades that depletion of the endoplasmic reticulum (ER) Ca 2+ store in nonexcitable cells activates Ca 2+ influx across the plasma membrane, a process known as 'store-operated calcium entry' (SOCE). SOCE is best exemplified by the highly Ca 2+ -selective calcium release-activated calcium (CRAC) channels. Rare gene alleles that compromise CRAC channel expression or activation result in severe immunodeficiency disease in human patients. The recent discovery of two major players of SOCE, STIM and ORAI, revolutionized our understanding of the molecular basis of this long-standing physiological mystery. The four-pass transmembrane protein ORAI constitutes the pore subunit of the CRAC channel and is gated by the ER-resident Ca 2+ sensor protein STIM through direct protein-protein interactions. Following the identification and biochemical and biophysical characterization of these two proteins, the major steps and certain regulatory mechanisms involved in the exquisite molecular choreography of SOCE have been worked out in great detail.
