Fine-tuning of store-operated calcium entry by fast and slow Ca-dependent inactivation: Involvement of SARAF.

Store-operated Ca entry (SOCE) is a functionally relevant mechanism for Ca influx present in electrically excitable and non-excitable cells. Regulation of Ca entry through store-operated channels is essential to maintain an appropriate intracellular Ca homeostasis and prevent cell damage. Calcium-release activated channels exhibit Ca-dependent inactivation mediated by two temporally separated mechanisms: fast Ca-dependent inactivation takes effect in the order of milliseconds and involves the interaction of Ca with residues in the channel pore while slow Ca-dependent inactivation (SCDI) develops over tens of seconds, requires a global rise in [Ca] and is a mechanism regulated by mitochondria. Recent studies have provided evidence that the protein SARAF (SOCE-associated regulatory factor) is involved in the mechanism underlying SCDI of Orai1. SARAF is an endoplasmic reticulum (ER) membrane protein that associates with STIM1 and translocate to plasma membrane-ER junctions in a STIM1-dependent manner upon store depletion to modulate SOCE. SCDI mediated by SARAF depends on the location of the STIM1-Orai1 complex within a PI(4,5)P-rich microdomain. SARAF also interacts with Orai1 and TRPC1 in cells endogenously expressing STIM1 and cells with a low STIM1 expression and modulates channel function. This review focuses on the modulation by SARAF of SOCE and other forms of Ca influx mediated by Orai1 and TRPC1 in order to provide spatio-temporally regulated Ca signals.