Regulation of CRAC channels by Ca2+-dependent inactivation

•CRAC channels, a major route for Ca2+ entry in many cell types, is regulated through Ca2+ −dependent inactivation mechanisms.•Ca2+ −dependent fast inactivation develops over milliseconds and reflects build-up of Ca2+ close to the channel pore.•Ca2+ −dependent slow inactivation develops over tens of seconds and requires a rise in global Ca2+. It is regulated by mitochondria and the ER-resident protein SARAF.•Recent advances in our understanding of the molecular bases of these inactivation pathways will be described.

CRAC channels are a major route for Ca2+ influx in eukaryotic cells. The channels show prominent Ca2+-dependent inactivation through two spatially and temporally distinct mechanisms: fast inactivation, which develops over milliseconds and is triggered by Ca2+ near the mouth of the channel and slow inactivation, which arises over tens of seconds and requires a rise in global cytosolic Ca2+. Slow inactivation is controlled physiologically by Ca2+ 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 Ca2+-dependent inhibitory pathways.

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