STIM and Orai: Dynamic Intermembrane Coupling to Control Cellular Calcium Signals

Ca2+ signals controlling a vast array of cell functions involve both Ca2+ store release and external Ca2+ entry. These two events are coordinated through a dynamic intermembrane coupling between two distinct membrane proteins, STIM and Orai. STIM proteins are endoplasmic reticulum (ER) luminal Ca2+ sensors that undergo a profound redistribution into discrete junctional ER domains closely juxtaposed with the plasma membrane (PM). Orai proteins are PM Ca2+ channels that migrate and become tethered by STIM within the ER-PM junctions, where they mediate exceedingly selective Ca2+ entry. We describe a new understanding of the nature of the proteins and how they function to mediate this remarkable intermembrane signaling process controlling Ca2+ signals.