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

Abstract

Store-operated Ca2+ entry (SOCE) is activated in response to the inositol-1,4,5-trisphosphate (InsP3)-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 (ICRAC), which is mediated by STIM1 and Orai1; (2) the store-operated non-selective current (ISOC), which is mediated by STIM1, TRPC1, and TRPC4; and (3) the moderately Ca2+-selective, ICRAC-like current, which is mediated by STIM1, TRPC1, TRPC4, and Orai1.

Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer

“…The transmembrane protein STIM1 interacts with ORAI1, which activates CRAC channels, which in turn activates Ca 2+ -selective Icrac currents. STIM1 interacts with TRPC1 to form the STIM-ORAI1-TRPC1 complex and activates the SOCC channel, which facilitates the formation of heterotetrames of the nonselective cation channels TRPC1, TRPC4, and TRPC5 to facilitate further calcium influx ( Moccia et al, 2023 ). It has been shown that TRPC1 is not sufficient to form channels when expressed on it ( Beech, 2013 ).…”

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

“…The I CRAC is the primary Ca 2+ -entry pathway sustaining intracellular Ca 2+ oscillations over time in non-excitable cells and mediates an influx of Ca 2+ that is commonly termed store-operated Ca 2+ entry (SOCE) [ 5 , 6 , 57 , 58 ]. SOCE is activated whenever the ER Ca 2+ concentration ([Ca 2+ ] ER ) in proximity of discrete sub-compartments of the peripheral ER falls below a threshold concentration because of ER Ca 2+ release through InsP 3 Rs [ 66 , 67 ].…”

“…SOCE is activated whenever the ER Ca 2+ concentration ([Ca 2+ ] ER ) in proximity of discrete sub-compartments of the peripheral ER falls below a threshold concentration because of ER Ca 2+ release through InsP 3 Rs [ 66 , 67 ]. SOCE is mediated by the physical interaction between two ubiquitously expressed proteins ( Figure 3 ): STIM, which is the sensor of [Ca 2+ ] ER , and Orai, which contributes the Ca 2+ -selective channel protein on the plasma membrane [ 5 , 6 , 68 ]. STIM presents two isoforms, i.e., STIM1 and STIM2, whereas Orai displays three paralogues, i.e., Orai1, Orai2, and Orai3.…”

“…Briefly, a reduction in [Ca 2+ ] ER stimulates STIM proteins to assemble into oligomers that redistribute to peripheral ER-plasma membrane junctions, known as puncta, while extending their cytosolic COOH-termini, which contain the STIM Orai-activating region/CRAC-activating domain (SOAR/CAD), towards the inner leaflet of the plasma membrane ( Figure 3 ). The SOAR/CAD domain, in turn, binds to and gates the hexameric Orai channels, thereby activating the I CRAC and inducing SOCE ( Figure 3 ) [ 5 , 6 , 69 ]. STIM2 presents a lower Ca 2+ affinity as compared to STIM1 and is, therefore, activated upon a modest fall in [Ca 2+ ] ER .…”

“…A crucial role in the pathogenic mechanism of ACM can be played by the fibro-adipogenic differentiation of cardiac mesenchymal stromal cells (C-MSCs), which renders the cardiac tissue more likely to develop the arrhythmic events leading to the patient’s death [ 2 , 3 ]. Intriguingly, a recent investigation showed that the I c antiarrhythmic drug (AAD) flecainide inhibited fibro-adipose differentiation in human C-MSCs (C-hMSCs) expanded from ACM patients (ACM C-hMSCs) by blocking store-operated Ca 2+ entry (SOCE) [ 4 ], which represents the most important Ca 2+ entry pathway in non-excitable cells [ 5 , 6 , 7 ], including MSCs [ 8 , 9 , 10 ]. Herein, we first describe the genetic background and therapeutic options of ACM.…”