STIM and Orai: dynamic intermembrane coupling to control cellular calcium signals.

Ca(2+) signals controlling a vast array of cell functions involve both Ca(2+) store release and external Ca(2+) 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 Ca(2+) sensors that undergo a profound redistribution into discrete junctional ER domains closely juxtaposed with the plasma membrane (PM). Orai proteins are PM Ca(2+) channels that migrate and become tethered by STIM within the ER-PM junctions, where they mediate exceedingly selective Ca(2+) entry. We describe a new understanding of the nature of the proteins and how they function to mediate this remarkable intermembrane signaling process controlling Ca(2+) signals.