Store-Operated Calcium Channels: From Function to Structure and Back Again

Store-operated calcium (Ca2+) entry (SOCE) occurs through a widely distributed family of ion channels activated by the loss of Ca2+ from the endoplasmic reticulum (ER). The best understood of these is the Ca2+ release-activated Ca2+ (CRAC) channel, which is notable for its unique activation mechanism as well as its many essential physiological functions and the diverse pathologies that result from dysregulation. In response to ER Ca2+ depletion, CRAC channels are formed through a diffusion trap mechanism at ER-plasma membrane (PM) junctions, where the ER Ca2+ sensing stromal interaction molecule (STIM) proteins bind and activate hexamers of Orai pore-forming proteins to trigger Ca2+ entry. Cell biological studies are clarifying the architecture of ER-PM junctions, their roles in Ca2+ and lipid transport, and functional interactions with cytoskeletal proteins. Key structural studies of STIM and Orai have inspired mutagenesis and electrophysiological approaches that now suggest novel mechanisms that control toggling of STIM between inactive and active states, models for STIM-Orai binding and channel gating, and how STIM binding to all six Orai channel subunits triggers opening while establishing signature CRAC channel characteristics including extremely high Ca2+ selectivity and low Ca2+ conductance.