Abstract
Store-operated Ca(2+) entry (SOCE) is activated in response to the inositol-1,4,5-trisphosphate (InsP(3))-dependent depletion of the endoplasmic reticulum (ER) Ca(2+) store and represents a ubiquitous mode of Ca(2+) 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 Ca(2+)-selective Ca(2+)-release activated Ca(2+) 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 Ca(2+)-selective, I(CRAC)-like current, which is mediated by STIM1, TRPC1, TRPC4, and Orai1.