The Molecular Heterogeneity of Store-Operated Ca2+ Entry in Vascular Endothelial Cells: The Different roles of Orai1 and TRPC1/TRPC4 Channels in the Transition from Ca2+-Selective to Non-Selective Cation Currents

Store-operated Ca2+ entry (SOCE) is activated in response to the inositol-1,4,5-trisphosphate (InsP(3))-dependent depletion of the endoplasmic reticulum (ER) Ca2+ store and represents a ubiquitous mode of Ca2+ influx. In vascular endothelial cells, SOCE regulates a plethora of functions that maintain cardiovascular homeostasis, such as angiogenesis, vascular tone, vascular permeability, platelet aggregation, and monocyte adhesion. The molecular mechanisms responsible for SOCE activation in vascular endothelial cells have engendered a long-lasting controversy. Traditionally, it has been assumed that the endothelial SOCE is mediated by two distinct ion channel signalplexes, i.e., STIM1/Orai1 and STIM1/Transient Receptor Potential Canonical 1(TRPC1)/TRPC4. However, recent evidence has shown that Orai1 can assemble with TRPC1 and TRPC4 to form a non-selective cation channel with intermediate electrophysiological features. Herein, we aim at bringing order to the distinct mechanisms that mediate endothelial SOCE in the vascular tree from multiple species (e.g., human, mouse, rat, and bovine). We propose that three distinct currents can mediate SOCE in vascular endothelial cells: (1) the Ca2+-selective Ca2+-release activated Ca2+ current (I-CRAC), which is mediated by STIM1 and Orai1; (2) the store-operated non-selective current (I-SOC), which is mediated by STIM1, TRPC1, and TRPC4; and (3) the moderately Ca2+-selective, I-CRAC-like current, which is mediated by STIM1, TRPC1, TRPC4, and Orai1.

Automated summary

Store-operated Ca2+ entry (SOCE) is a ubiquitous mode of Ca2+ influx that regulates various functions in vascular endothelial cells. The activation mechanisms of endothelial SOCE have been controversial, with traditional assumptions of two distinct ion channels complexes, STIM1/Orai1 and STIM1/TRPC1/TRPC4. Recent evidence suggests that Orai1 can assemble with TRPC1 and TRPC4 to form a non-selective cation channel. Here, we summarize the different mechanisms of endothelial SOCE in the vascular tree of multiple species, proposing the involvement of three distinct currents mediated by STIM1, Orai1, TRPC1, and TRPC4.