Structure, Regulation and Biophysics of ICRAC, STIM/Orai1

Ca2+ release activated Ca2+ (CRAC) channels mediate robust Ca2+ influx when the endoplasmic reticulum Ca2+ stores are depleted. This essential process for T-cell activation as well as degranulation of mast cells involves the Ca2+ sensor STIM1, located in the endoplasmic reticulum and the Ca2+ selective Orai1 channel in the plasma membrane. Our review describes the CRAC signaling pathway, the activation of which is initiated by a drop in the endoplasmic Ca2+ level sensed by STIM1. This in term induces multimerisation and puncta-formation of STIM1 proteins is followed by their coupling to and activation of Orai channels. Consequently Ca2+ entry is triggered through the Orai pore into the cytosol with subsequent closure of the channel by Ca2+-dependent inactivation. We will portray a mechanistic view of the events coupling STIM1 to Orai activation based on their structure and biophysics.