Store-Operated Calcium Channels

Abstract

Store-operated calcium (SOC) channels mediate calcium (Ca2+) influx from the extracellular environment into the cell cytosol upon depletion of endoplasmic reticulum (ER) Ca2+ stores. The molecular components responsible for SOC entry (SOCE) remained a mystery until two recent discoveries. RNA-interference (RNAi) screening of candidate genes led first to the discovery of dStim/STIM1, an ER-resident transmembrane protein responsible for mediating the signal that activates SOCE. Genome-wide RNAi screening then led to identification of the ORAI proteins that form the Ca2+-selective pore of the SOC channel known as the calcium release-activated calcium channel. STIM dimers sense ER Ca2+ store depletion through Ca2+ unbinding from STIM's low-affinity, N-terminal EF-hand in the lumen of the ER. This induces STIM dimers to oligomerize and to translocate toward the plasma membrane (PM). STIM then forms dense clusters at ER–PM junctions, organizes ORAI dimers into tetramers in mirror-image PM clusters, and finally activates ORAI tetramers to conduct Ca2+ selectively across the PM. STIM proteins also organize canonical transient receptor potential channels into clusters and open them to bring about SOCE through Ca2+-permeable but relatively nonselective pores. STIM proteins serve multiple signaling functions that have important biomedical implications, particularly in the immune system.