Molecular Basis and Regulation of Store-Operated Calcium Entry

Store-operated Ca²⁺ entry (SOCE) is a ubiquitous mechanism for Ca²⁺ influx in mammalian cells with important physiological implications. Since the discovery of SOCE more than three decades ago, the mechanism that communicates the information about the amount of Ca²⁺ accumulated in the intracellular Ca²⁺ stores to the plasma membrane channels and the nature of these channels have been matters of intense investigation and debate. The stromal interaction molecule-1 (STIM1) has been identified as the Ca²⁺ sensor of the intracellular Ca²⁺ compartments that activates the store-operated channels. STIM1 regulates two types of store-dependent channels: the Ca²⁺ release-activated Ca²⁺ (CRAC) channels, formed by Orai1 subunits, that conduct the highly Ca²⁺ selective current I _CRAC and the cation permeable store-operated Ca²⁺ (SOC) channels, which consist of Orai1 and TRPC1 proteins and conduct the non-selective current I _SOC. While the crystal structure of Drosophila CRAC channel has already been solved, the architecture of the SOC channels still remains unclear. The dynamic interaction of STIM1 with the store-operated channels is modulated by a number of proteins that either support the formation of the functional STIM1-channel complex or protect the cell against Ca²⁺ overload.