Regulation of CRAC channels by Ca-dependent inactivation.

CRAC channels are a major route for Ca influx in eukaryotic cells. The channels show prominent Ca-dependent inactivation through two spatially and temporally distinct mechanisms: fast inactivation, which develops over milliseconds and is triggered by Ca near the mouth of the channel and slow inactivation, which arises over tens of seconds and requires a rise in global cytosolic Ca. Slow inactivation is controlled physiologically by Ca uptake into mitochondria through the MCU. Site-directed mutagenesis studies on STIM1 and Orai1 have led to new molecular insight into how fast inactivation occurs. This review describes properties and molecular mechanisms that contribute to these important Ca-dependent inhibitory pathways.