Molecular modulators of store-operated calcium entry

Three decades ago, store-operated Ca2 + entry (SOCE) was identified as a unique mechanism for Ca2 + entry through plasma membrane (PM) Ca2 +-permeable channels modulated by the intracellular Ca2 + stores, mainly the endoplasmic reticulum (ER). Extensive analysis of the communication between the ER and the PM leads to the identification of the protein STIM1 as the ER-Ca2 + sensor that gates the Ca2 + channels in the PM. Further analysis on the biophysical, electrophysiological and biochemical properties of STIM1-dependent Ca2 + channels has revealed the presence of a highly Ca2 +-selective channel termed Ca2 + release-activated Ca2 + channel (CRAC), consisting of Orai1 subunits, and non-selective cation channels named store-operated channels (SOC), including both Orai1 and TRPC channel subunits. Since the identification of the key elements of CRAC and SOC channels a number of intracellular modulators have been reported to play essential roles in the stabilization of STIM-Orai interactions, collaboration with STIM1 conformational changes or mediating slow Ca2 +-dependent inactivation. Here, we review our current understanding of some of the key modulators of STIM1-Orai1 interaction, including the proteins CRACR2A, STIMATE, SARAF, septins, golli and ORMDL3.