Orai is a highly (Ca
2+)-selective ion channel in the plasma membrane formed by four transmembrane domains. Orai family includes Orai1, Orai2, and Orai3
[8]. The calcium release-activated calcium (CRAC) channels are composed of Orai and STIM, representing a typical voltage independent store-operated Ca
2+ entry (SOCE)
[32][33][33,34]. Store-operated Ca
2+ channels fine tune Ca
2+ entry in both cardiomyocytes and SMCs, and they are activated once the Ca
2+ store in ER or sarcoplasmic reticulum (SR) is depleted or the level of cytosolic Ca
2+ is lowered, thereby facilitating agonist-induced Ca
2+ influx. It has also been suggested that STIM1, Orai and TRPC channels could form the molecular basis of SOCE in some types of cells and their intricate interactions control the entry of Ca
2+ into cells to regulate numerous physiological processes
[34][35]. Orai1 in plasma membrane and STIM1 in ER conduct Orai-STIM signaling at the membrane junction between ER and plasma membrane, and they are the bona fide molecular components of SOCE and CRAC
[8][35][8,36]. Once the ER Ca
2+ store is depleted, STIM1 protein can move to the plasma membrane and activate Orai and TRPC channels, allowing extracellular Ca
2+ to enter the cytoplasm
[8][35][8,36]. Orai2 and Orai3 channels have been discovered to be key players in regenerative Ca
2+ oscillations induced by physiological receptor activation, while Orai1 is not necessarily involved in this process. However, the binding of Orai2 and Orai3 to Orai1 could expand the sensitivity range of receptor-activated Ca
2+ signals
[36][37].
Orai plays a critical role in regulating cardiovascular function in both health and disease
[34][37][38][35,38,39]. Orai1 protein deficiency leads to heart failure in zebrafish
[39][40]. The knockout of Orai3 in cardiomyocyte causes dilated cardiomyopathy and heart failure in mice
[40][41]. Both Orai1 and Orai3 are the phenotype modulators of vascular SMCs. Orai1 is upregulated in SMCs during vascular injury. The downregulation of Orai1 inhibits SMC proliferation and reduces neointima formation following balloon injury of rat carotids
[41][42]. Orai3 is also upregulated in neointimal SMCs in rat balloon injured carotid artery, and the knockdown of Orai3 inhibits neointima formation
[42][43]. The transformation of vascular SMC phenotypes is one of the pathological characteristics in chronic hypertension, and the synergistic action between Orai and STIM mediates Ca
2+ entry and drives the fibroproliferative gene program
[43][44]. Orai facilitates Ca
2+ entry and is a potential therapeutic target for the treatment of hypertension
[34][35]. Most cardiovascular diseases are closely associated with cellular remodeling, and Ca
2+ signaling pathways have emerged as important regulators of smooth muscle, endothelial, epithelial, platelet, and immune cell remodeling
[44][45]. Ca
2+-permeable Orai channel is also important for endothelial cell proliferation and angiogenesis
[45][46][46,47]. In terms of vascular physiology and functional regulation, Orai1 appears to trigger the increase of vascular permeability, which is an early marker of atherogenesis. Knockdown of Orai1 reduces the histone 1-induced hyperpermeability in endothelial cells
[47][48]. ApoE knockout mice are a common model for atherosclerosis. A high fat diet can upregulate the expression of Orai1 mRNA and protein in aortic tissue. SiRNA knockdown of Orai1 can reduce the size of atherosclerotic plaque
[48][49]. The migration of neutrophil is another hallmark in atherosclerosis, and during this process Orai1 is required for neutrophil migration to the inflammatory endothelium
[44][45]. All these experimental evidence show that Orai1 expression is associated with development of atherogenesis. Moreover, Orai often acts in conjunction with STIM to form CRAC, which can be responsible for many physiological functions or the development of various cardiovascular diseases
[34][38][49][35,39,50].