Ca2+ Proteins in Cardiovascular Disease

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		XiaoYong Tong	+ 2895 word(s)	2895	2021-09-27 08:47:15	\|
2	Format change	Jessie Wu	Meta information modification	2895	2021-10-08 03:20:23	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms22168782

Mechanosensitive ion channels are widely expressed in the cardiovascular system. They translate mechanical forces including shear stress and stretch into biological signals. The most prominent biological signal through which the cardiovascular physiological activity is initiated or maintained are intracellular calcium ions (Ca2+). Growing evidence show that the Ca2+ entry mediated by mechanosensitive ion channels is also precisely regulated by a variety of key proteins which are distributed in the cell membrane or endoplasmic reticulum. Recent studies have revealed that mechanosensitive ion channels can even physically interact with Ca2+ regulatory proteins and these interactions have wide implications for physiology and pathophysiology.

mechanosensitive ion channels Piezo channels TRP channels

1. Introduction

Despite decades of efforts, cardiovascular disease is still the number one killer in the world. The latest data show that one in six elderly people dies of cardiovascular disease. In 2019, ischemic heart disease and stroke were reported to be the leading causes for disability in the age groups of 50–74 and 75 years or above ^[1]. As a dominant second messenger, Ca²⁺ plays an important role in the cardiovascular health and diseases. For example, dietary calcium supplement and its retention reduce cardiovascular response to sodium stress in Black people ^[2]. There are still some controversies over the cardiovascular effects of high Ca²⁺ intake in the diet, and whether the relationship between Ca²⁺ intake and cardiovascular disease risk is J- or U-shape ^[3]. Ca²⁺ is pivotal in maintaining the functions of endothelial cells, smooth muscle cells (SMCs) and cardiomyocytes. It controls the contraction or relaxation of arteries and heart and regulates blood pressure and cardiac functions ^[4]^[5]^[6]^[7].

The cell membrane controls the balance between intracellular and extracellular Ca²⁺ via various proteins, and thus maintains Ca²⁺ homeostasis. Plasma membrane Ca²⁺ ATPase (PMCA), voltage-gated calcium channel (VGCC), Na⁺/Ca²⁺ exchanger (NCX), and Orai have been identified as the main calcium regulatory proteins on the cell membrane ^[8]^[9]^[10]^[11]. Endoplasmic reticulum (ER) as an important Ca²⁺ reservoir in the cell also contains some calcium regulatory proteins. Such proteins in the ER include stromal interaction molecules (STIM), inositol 1,4,5-trisphosphate receptor (IP3R), and sarco/endoplasmic reticulum calcium-ATPase (SERCA). All these proteins are critical in controlling cell functions, such as growth, migration, apoptosis, and metabolism ^[12]^[13]^[14]. As a general feedback mechanism, these key Ca²⁺ regulatory proteins are also regulated by intracellular Ca²⁺ level.

Mechanical forces are crucial for cardiovascular functions and therefore the discoveries of mechanosensitive ion channels represent a major breakthrough in understanding cardiovascular mechanobiology. In particular, the endothelium in the cardiovascular system is subjected to regular mechanical stimulus evoked by blood flow. The discovered mechanosensitive ion channels including Piezo channels and transient receptor potential (TRP) channels can conduct the entry of cationic ions, particularly Ca²⁺, in response to the stimulus from shear stress of blood flow ^[15]^[16]. Both Piezo and TRP channels are closely linked to the development of cardiovascular disease. In some cardiovascular diseases, such as hypertension, atherosclerosis, or aneurysmal plaques, altered mechanical stress which can directly activate mechanosensitive ion channels has been reported ^[17].

2. Ca²⁺ Regulatory Proteins in Cardiovascular System

2.1. NCX

NCX mainly works in the forward mode, which uses the electrochemical gradient driven by Na⁺ to expel Ca²⁺ from cells in order to maintain the concentration of Ca²⁺ required for physiological activities, and the ion stoichiometric ratio is 3Na⁺:1Ca²⁺ ^[18]. There are three types of NCX: NCX1, NCX2, and NCX3 ^[19]. Structural studies revealed that eukaryotic NCX protein consists of 10 transmembrane helixes. There is a large cytoplasmic regulatory loop between transmembrane helix 5 and 6. This loop includes two regulatory (Ca²⁺)-binding domains 1 and 2 ^[20]^[21], which adjust the rate of from cells to adapt to the dynamic Ca²⁺ oscillation ^[20]^[22]^[23]. The Ca²⁺ extrusion usually leads to smooth muscle relaxation, so that the vascular tension is reduced ^[24]. However, under some extreme conditions, such as high concentration of intracellular Na⁺ or high positive membrane potential, NCX works in a reverse mode to evoke Ca²⁺ influx instead of the typical extrusion ^[22], which can then lead to contraction of SMCs and artery ^[25]^[26]. Interestingly, the forward mode of NCX can be changed to its reverse mode by the increase of cytosolic Na⁺ and membrane potential ^[27], suggesting a feedback regulatory mechanism may exist ^[18].

NCX regulates many essential physiological events, such as muscle excitation-contraction or blood pressure regulation ^[28]^[29]. The deletion of NCX causes the loss of NCX function in myocardium and consequentially results in embryonic death ^[24]. The altered expression and regulation of NCXs could disrupt Ca²⁺ homeostasis and initiate molecular and cellular remodeling in various tissues, which is related to hypertension and heart failure. Inhibitors of NCX can improve myocardial function in patients with heart failure and bring the Ca²⁺ hyper-responsiveness back to normal in vascular SMCs from hypertensive patients ^[25]^[30]. NCX1 in smooth muscle and endothelium could play opposite roles in regulating blood pressure. Arterial blood pressure is correlated with the expression level of NCX1 in vascular SMCs ^[25]. The increased expression of vascular NCX1 is associated with the vasoconstriction in several animal models of salt-dependent hypertension ^[25]. Furthermore, reduced arterial myogenic tone and low blood pressure were observed in vascular smooth muscle NCX1 conditional knockout mice. However, for the mice with NCX1 overexpression in vascular SMCs, high blood pressure and vasoconstriction even accompanied with increased expression of transient receptor potential canonical channel (TRPC) 6 were reported ^[25], which suggests that NCX could control arterial constriction and regulate blood pressure by cross-talking to TRPC6 channels ^[25]. In the mesentery constricted by phenylephrine, antagonists of NCX reverse mode eliminate acetylcholine-evoked nitric oxide production in intact mesenteric arteries and inhibit acetylcholine- or ATP-induced increase of intracellular Ca²⁺ in cultured endothelial cells, indicating that the activation of NCX reverse mode can play an important role in mediating the acetylcholine-induced vasodilation in resistance arterial endothelial cells ^[31].

2.2. Orai

Orai is a highly (Ca²⁺)-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 Ca²⁺ entry (SOCE) ^[32]^[33]. Store-operated Ca²⁺ channels fine tune Ca²⁺ entry in both cardiomyocytes and SMCs, and they are activated once the Ca²⁺ store in ER or sarcoplasmic reticulum (SR) is depleted or the level of cytosolic Ca²⁺ is lowered, thereby facilitating agonist-induced Ca²⁺ 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 Ca²⁺ into cells to regulate numerous physiological processes ^[34]. 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]. Once the ER Ca²⁺ store is depleted, STIM1 protein can move to the plasma membrane and activate Orai and TRPC channels, allowing extracellular Ca²⁺ to enter the cytoplasm ^[8]^[35]. Orai2 and Orai3 channels have been discovered to be key players in regenerative Ca²⁺ 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 Ca²⁺ signals ^[36].

Orai plays a critical role in regulating cardiovascular function in both health and disease ^[34]^[37]^[38]. Orai1 protein deficiency leads to heart failure in zebrafish ^[39]. The knockout of Orai3 in cardiomyocyte causes dilated cardiomyopathy and heart failure in mice ^[40]. 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]. Orai3 is also upregulated in neointimal SMCs in rat balloon injured carotid artery, and the knockdown of Orai3 inhibits neointima formation ^[42]. The transformation of vascular SMC phenotypes is one of the pathological characteristics in chronic hypertension, and the synergistic action between Orai and STIM mediates Ca²⁺ entry and drives the fibroproliferative gene program ^[43]. Orai facilitates Ca²⁺ entry and is a potential therapeutic target for the treatment of hypertension ^[34]. Most cardiovascular diseases are closely associated with cellular remodeling, and Ca²⁺ signaling pathways have emerged as important regulators of smooth muscle, endothelial, epithelial, platelet, and immune cell remodeling ^[44]. Ca²⁺-permeable Orai channel is also important for endothelial cell proliferation and angiogenesis ^[45]^[46]. 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]. 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]. The migration of neutrophil is another hallmark in atherosclerosis, and during this process Orai1 is required for neutrophil migration to the inflammatory endothelium ^[44]. 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].

2.3. STIM

STIM is a single pass transmembrane protein residing in the ER. It contains two homologous proteins, STIM1 and STIM2 ^[50]^[51]. The function of STIM is to sense the concentration of Ca²⁺ in ER and makes appropriate response through conformational change to regulate Ca²⁺ homeostasis ^[38]^[52]. STIM1 stays at a closed state when ER lumen is filled with Ca²⁺ and transitions to an open state when Ca²⁺ in the ER lumen is decreased ^[53]. The Ca²⁺-sensitive domain in the STIM N-terminal senses Ca²⁺ level of ER ranging from 100 to 400 µM ^[51]^[54], and the C-terminal of STIM interacts with Orai to form CRAC channel to induce Ca²⁺ influx ^[51]^[55]. As mentioned above, the interactions between STIM1 and Orai1 regulate physiological and pathological functions ^[34]^[38]^[49].

STIM is involved in both the cardiac physiological functions and the cardiac disease development. STIM is essential for the maintenance of myocardial contractility, and its knockout leads to a reduction in left ventricular contractility. STIM1 is expressed more abundantly in early cardiomyocytes than in somatic cells. Cardiomyocyte-STIM1-specific knockout mice exhibit dilated cardiomyopathy and cardiac fibrosis with increased stress biomarkers and altered organelle morphology in the heart, suggesting that STIM1 can regulate myocardial development and heart function ^[38]. However, the spatially differential distribution of STIM1-triggered Ca²⁺ signaling generates the Ca²⁺ microdomain that regulates myofilament remodeling and activates pro-hypertrophic factors locally, and as a consequence, pathological cardiac hypertrophy is induced ^[56]. The STIM1-guided Ca²⁺ signaling is also involved in thrombosis. The aggregation of platelets at the site of thrombosis requires the increase of intracellular Ca²⁺ concentration. STIM1 is involved in this process through maintaining a high Ca²⁺ concentration. In addition, STIM1 stabilizes the thrombus by promoting the expression of phosphatidylserine in plasma membrane ^[38]^[57]. The upregulation of STIM induces fibroproliferative gene expression and vascular SMC remodeling, which eventually leads to chronic hypertension ^[43]. The cell proliferation and migration promoted by STIM1 are also involved in atherosclerosis ^[58]^[59]. Oxidized low-density lipoprotein (ox-LDL) can increase the expression of STIM1, and then promote cell proliferation and migration in mouse aortic SMCs. Silencing STIM1 inhibits ox-LDL-induced cell proliferation and migration and hence suppresses atherosclerosis ^[58]^[59]. The role of STIM1 in the pathogenesis of these diseases suggests that specific inhibition of STIM1 may contribute to the treatment of these diseases. STIM2 is another important protein for health. Studies on STIM2 deficient mice show that they gradually die from 4 to 8 weeks ^[60].STIM2 has similar functional effects to STIM1 in some aspects. Both proteins can promote vascular remodeling by inducing the transformation of phenotypes in pulmonary artery SMCs ^[61].

2.4. IP3R

IP3R is a tetrameric channel consisting of four glycoproteins in the ER or SR. So far, three types of IP3R channels have been identified: IP3R1, IP3R2, and IP3R3 ^[62]. IP3R has four structural regions: IP3 binding region, central regulatory region, transmembrane domain, and C-terminal region. It can be activated by the selective ligand inositol 1,4,5-triphosphate (IP3) and is permeable to Ca²⁺ ^[63]. All these isoforms of IP3R can be expressed in vascular SMCs. They are important for the physiological functioning of the cardiovascular system ^[64]. IP3R is one of the major sources for intracellular Ca²⁺ release. The overexpression of IP3R enhances ER Ca²⁺ depletion, which reduces ER intraluminal Ca²⁺ concentration in the vicinity of STIM1 and then activates Orai ion channels ^[65]. In response to increased IP3 or decreased Ca²⁺ in ER, IP3Rs empty Ca²⁺ stored in the ER and activate Ca²⁺ inward flow ^[66]. IP3R also functions on the membrane contact sites between ER and mitochondria to transport Ca²⁺ from ER to mitochondria. Each isoform of IP3R can mediate this contact and Ca²⁺ transport, but IP3R2 is the most efficient one in delivering Ca²⁺ to mitochondria from ER ^[67]^[68]. The voltage-dependent anion channel on the outer mitochondrial membrane can also enhance Ca²⁺ accumulation through physical interaction with IP3R ^[69], which is vital for the maintenance of mitochondrial function.

Under physiological conditions, IP3R signal controls the contraction, migration, and proliferation of vascular SMCs. However, under the pathological conditions, IP3R is involved in the development of atherosclerosis and hypertension ^[70]. IP3R is activated following the stimulation of G-protein coupled receptors and binds to STIM1 upon Ca²⁺ depletion in ER. The association of IP3R-STIM1 increases Ca²⁺ inward flow ^[65]. When IP3 binds with IP3Rs, vasoconstriction and hypertension can be induced as a consequence to the increased concentration of cytoplasmic Ca²⁺ released from the ER. The deletion of IP3Rs reduces the contractile response to vasoconstrictors and even reverses the pathological states ^[64]. In the heart, IP3R-mediated Ca²⁺ release ensures the integrity of cardiac excitation-contraction coupling, which forms the basis of the heartbeat ^[71]. The dysfunction of IP3R in cardiomyocytes leads to the disturbance of local Ca²⁺ homeostasis, which is closely related to congenital diseases, increased risk of arrhythmia, decreased contractility, or heart failure related arrhythmias ^[72]. The expression of IP3R is upregulated in atrial fibrillation, and inhibition of IP3R can significantly reduce the occurrence and duration of atrial fibrillation. Therefore, IP3R may emerge as a new target for the treatment of atrial fibrillation ^[73].

2.5. SERCA

SERCA is a Ca²⁺ transporter located on SR/ER and is mainly responsible for the transport of cytoplasmic Ca²⁺ back to SR/ER. SERCA isoform is encoded by SERCA1, SERCA2, or SERCA3 genes. Each isoform may have differential roles in different tissues or cells ^[74]. There are four functional domains (M, N, P, and A) and a polypeptide chain in SERCA protein. The M domain contains transmembrane components and Ca²⁺ binding sites, while N, P and A located in the sarcoplasm are responsible for ATP hydrolysis ^[75]. Each ATP hydrolysis can transport 2 Ca²⁺ to the ER lumen in exchange for 1 H⁺ ^[76]. SERCA2a is the major isoform of cardiac SERCA, while SERCA2b is the major one of vascular SERCA.

The influx of Ca²⁺ into SR/ER mediated by SERCA2 is necessary for the relaxation of cardiomyocytes and blood vessels. The disruption of SERCA2 activity leads to ER stress and cardiovascular disease ^[75]. Hormones, phospholamban and sarcolipin are the common regulators of SERCA. Especially, phospholamban plays a major role in regulating SERCA, and its interaction with SERCA2a reduces the binding affinity of SERCA2a to Ca²⁺ at low cytoplasmic Ca²⁺ concentration ^[77]. The downregulation of SERCA2a is found in failing heart and atherosclerotic vessels ^[78]. The decreased protein level of SERCA2a and p16-phospholamban leads to left ventricular diastolic dysfunction and elevated arterial blood pressure ^[79]. Activation of SERCA can accelerate the reuptake of Ca²⁺ by SR, which would improve the diastolic dysfunction of myocardium, and result in strong antiarrhythmic effect ^[80]^[81]. Our groups found that the S-glutathiolation of the amino acid residue Cys674 (C674) is key to the increase of the activity in SERCA2 under physiological conditions ^[82]^[83], but this post-translational protein modification is prevented by the irreversible oxidation of C674 thiol in pathology hallmarked by high level of ROS, including atherosclerosis, aortic aneurysms, aging and hypertension ^[82]^[84]^[85]^[86]. The substitution of the SERCA2 C674 by serine causes impaired angiogenesis following hindlimb ischemia by interrupting the physiological functions of endothelial cells and macrophage ^[87]^[88], increases blood pressure by inducing sodium retention and ER stress in the kidney ^[86], exacerbates angiotensin II-induced aortic aneurysm by switching the phenotypes in aortic SMCs ^[89], aggravates high fat diet-induced aortic atherosclerosis by evoking inflammatory response in endothelial cells and macrophage (our unpublished data), promotes pulmonary vascular remodeling, and protects against left ventricular dilation caused by chronic ascending aortic constriction ^[90]. All these data imply that the redox state of C674 and the function of SERCA2 are critical to the maintenance of cardiovascular homeostasis.

Currently, there are some ongoing clinical trials for the drugs specifically targeting these Ca²⁺ regulatory proteins in the cardiovascular system, as shown in Table 1. These trials provide promising opportunities for the treatment of cardiovascular diseases.

Table 1. Current clinical trials for drugs targeting these Ca²⁺ regulatory proteins in the cardiovascular system according to the ClinicalTrials.gov website (available online and accessed on 12 August 2021).

Ca²⁺ Regulatory Proteins	Treatment	Cardiovascular Disease	Phase
SERCA	AAV1/SERCA2a (MYDICAR) ^[91]	Ischemic cardiomyopathy; non-ischemic cardiomyopathy; heart failure; cardiomyopathies	Phase 2
	MYDICAR-single intracoronary infusion ^[92]	Heart failure, congestive; ischemic cardiomyopathy; non-ischemic cardiomyopathy	Phase 2
	MYDICAR ^[93]	Chronic heart failure	Phase 2
	SRD-001 ^[94]	Congestive and systolic heart failure	Phase 1/Phase 2
	Istaroxime ^[95]	Heart failure ^[96]	Early phase 1
NCX	MYDICAR ^[97]	Chronic heart failure	Phase 2
Orai	No resource	No resource	No resource
STIM	No resource	No resource	No resource
IP3R	No resource	No resource	No resource

References

Vos, T.; Lim, S.S.; Abbafati, C.; Abbas, K.M.; Abbasi, M.; Abbasifard, M.; Abbasi-Kangevari, M.; Abbastabar, H.; Abd-Allah, F.; Abdelalim, A.; et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020, 396, 1204–1222.
Ernst, F.A.; Enwonwu, C.O.; Francis, R.A. Calcium attenuates cardiovascular reactivity to sodium and stress in blacks. Am. J. Hypertens. 1990, 3 Pt 1, 451–457.
Mohammadifard, N.; Gotay, C.; Humphries, K.H.; Ignaszewski, A.; Esmaillzadeh, A.; Sarrafzadegan, N. Electrolyte minerals intake and cardiovascular health. Crit. Rev. Food Sci. Nutr. 2019, 59, 2375–2385.
Ottolini, M.; Hong, K.; Sonkusare, S.K. Calcium signals that determine vascular resistance. Wiley Interdiscip. Rev. Syst. Biol. Med. 2019, 11, e1448.
Wilson, C.; Zhang, X.; Buckley, C.; Heathcote, H.R.; Lee, M.D.; McCarron, J.G. Increased vascular contractility in hypertension results from impaired endothelial calcium signaling. Hypertension 2019, 74, 1200–1214.
Gusev, K.O.; Vigont, V.V.; Grekhnev, D.A.; Shalygin, A.V.; Glushankova, L.N.; Kaznacheeva, E.V. Store-operated calcium entry in mouse cardiomyocytes. Bull. Exp. Biol. Med. 2019, 167, 311–314.
Gorski, P.A.; Kho, C.; Oh, J.G. Measuring cardiomyocyte contractility and calcium handling in vitro. Methods Mol. Biol. 2018, 1816, 93–104.
Trebak, M.; Putney, J.W., Jr. ORAI calcium channels. Physiology 2017, 32, 332–342.
Lariccia, V.; Piccirillo, S.; Preziuso, A.; Amoroso, S.; Magi, S. Cracking the code of sodium/calcium exchanger (NCX) gating: Old and new complexities surfacing from the deep web of secondary regulations. Cell Calcium 2020, 87, 102169.
Ferreira-Gomes, M.S.; Mangialavori, I.C.; Ontiveros, M.Q.; Rinaldi, D.E.; Martiarena, J.; Verstraeten, S.V.; Rossi, J. Selectivity of plasma membrane calcium ATPase (PMCA)-mediated extrusion of toxic divalent cations in vitro and in cultured cells. Arch. Toxicol. 2018, 92, 273–288.
Gilbert, G.; Courtois, A.; Dubois, M.; Cussac, L.A.; Ducret, T.; Lory, P.; Marthan, R.; Savineau, J.P.; Quignard, J.F. T-type voltage gated calcium channels are involved in endothelium-dependent relaxation of mice pulmonary artery. Biochem. Pharmacol. 2017, 138, 61–72.
Krebs, J.; Agellon, L.B.; Michalak, M. Ca2+ homeostasis and endoplasmic reticulum (ER) stress: An integrated view of calcium signaling. Biochem. Biophys. Res. Commun. 2015, 460, 114–121.
Marchi, S.; Patergnani, S.; Missiroli, S.; Morciano, G.; Rimessi, A.; Wieckowski, M.R.; Giorgi, C.; Pinton, P. Mitochondrial and endoplasmic reticulum calcium homeostasis and cell death. Cell Calcium 2018, 69, 62–72.
Schachter, M. Vascular smooth muscle cell migration, atherosclerosis, and calcium channel blockers. Int. J. Cardiol. 1997, 62 (Suppl. 2), S85–S90.
Chubinskiy-Nadezhdin, V.I.; Vasileva, V.Y.; Pugovkina, N.A.; Vassilieva, I.O.; Morachevskaya, E.A.; Nikolsky, N.N.; Negulyaev, Y.A. Local calcium signalling is mediated by mechanosensitive ion channels in mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2017, 482, 563–568.
Ilkan, Z.; Wright, J.R.; Goodall, A.H.; Gibbins, J.M.; Jones, C.I.; Mahaut-Smith, M.P. Evidence for shear-mediated Ca2+ entry through mechanosensitive cation channels in human platelets and a megakaryocytic cell line. J. Biol. Chem. 2017, 292, 9204–9217.
Beech, D.J.; Kalli, A.C. Force sensing by Piezo channels in cardiovascular health and disease. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 2228–2239.
Giladi, M.; Tal, I.; Khananshvili, D. Structural features of ion transport and allosteric regulation in Sodium-Calcium Exchanger (NCX) proteins. Front. Physiol. 2016, 7, 30.
Héja, L.; Kardos, J. NCX activity generates spontaneous Ca2+ oscillations in the astrocytic leaflet microdomain. Cell Calcium 2020, 86, 102137.
Hilge, M.; Aelen, J.; Vuister, G.W. Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors. Mol. Cell 2006, 22, 15–25.
Liao, J.; Li, H.; Zeng, W.; Sauer, D.B.; Belmares, R.; Jiang, Y. Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger. Science 2012, 335, 686–690.
Blaustein, M.P.; Lederer, W.J. Sodium/calcium exchange: Its physiological implications. Physiol. Rev. 1999, 79, 763–854.
Philipson, K.D.; Nicoll, D.A. Sodium-calcium exchange: A molecular perspective. Annu. Rev. Physiol. 2000, 62, 111–133.
Nishimura, J. Topics on the Na+/Ca2+ exchanger: Involvement of Na+/Ca2+ exchanger in the vasodilator-induced vasorelaxation. J. Pharmacol. Sci. 2006, 102, 27–31.
Zhang, J. New insights into the contribution of arterial NCX to the regulation of myogenic tone and blood pressure. Adv. Exp. Med. Biol. 2013, 961, 329–343.
Li, M.; Shang, Y.X. Neurokinin-1 receptor antagonist decreases i in airway smooth muscle cells by reducing the reverse-mode Na+/Ca2+ exchanger current. Peptides 2019, 115, 69–74.
Alves-Lopes, R.; Neves, K.B.; Anagnostopoulou, A.; Rios, F.J.; Lacchini, S.; Montezano, A.C.; Touyz, R.M. Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (Transient Receptor Potential Melastatin 2) cation channel. Hypertension 2020, 75, 139–149.
Khananshvili, D. Sodium-calcium exchangers (NCX): Molecular hallmarks underlying the tissue-specific and systemic functions. Pflug. Arch. Eur. J. Physiol. 2014, 466, 43–60.
Filadi, R.; Pozzan, T. Generation and functions of second messengers microdomains. Cell Calcium 2015, 58, 405–414.
Primessnig, U.; Bracic, T.; Levijoki, J.; Otsomaa, L.; Pollesello, P.; Falcke, M.; Pieske, B.; Heinzel, F.R. Long-term effects of Na+ /Ca2+ exchanger inhibition with ORM-11035 improves cardiac function and remodelling without lowering blood pressure in a model of heart failure with preserved ejection fraction. Eur. J. Heart Fail. 2019, 21, 1543–1552.
Lillo, M.A.; Gaete, P.S.; Puebla, M.; Ardiles, N.M.; Poblete, I.; Becerra, A.; Simon, F.; Figueroa, X.F. Critical contribution of Na+-Ca2+ exchanger to the Ca2+-mediated vasodilation activated in endothelial cells of resistance arteries. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2018, 32, 2137–2147.
Gudlur, A.; Hogan, P.G. The STIM-Orai pathway: Orai, the pore-forming subunit of the CRAC channel. Adv. Exp. Med. Biol. 2017, 993, 39–57.
Nguyen, N.T.; Han, W.; Cao, W.M.; Wang, Y.; Wen, S.; Huang, Y.; Li, M.; Du, L.; Zhou, Y. Store-operated calcium entry mediated by ORAI and STIM. Compr. Physiol. 2018, 8, 981–1002.
Bhullar, S.K.; Shah, A.K.; Dhalla, N.S. Store-operated calcium channels: Potential target for the therapy of hypertension. Rev. Cardiovasc. Med. 2019, 20, 139–151.
Choi, S.; Maleth, J.; Jha, A.; Lee, K.P.; Kim, M.S.; So, I.; Ahuja, M.; Muallem, S. The TRPCs-STIM1-Orai interaction. Handb. Exp. Pharmacol. 2014, 223, 1035–1054.
Yoast, R.E.; Emrich, S.M.; Zhang, X.; Xin, P.; Johnson, M.T.; Fike, A.J.; Walter, V.; Hempel, N.; Yule, D.I.; Sneyd, J.; et al. The native ORAI channel trio underlies the diversity of Ca2+ signaling events. Nat. Commun. 2020, 11, 2444.
Zhang, W.; Trebak, M. STIM1 and Orai1: Novel targets for vascular diseases? Sci. China Life Sci. 2011, 54, 780–785.
Tanwar, J.; Trebak, M.; Motiani, R.K. Cardiovascular and hemostatic disorders: Role of STIM and Orai proteins in vascular disorders. Adv. Exp. Med. Biol. 2017, 993, 425–452.
Völkers, M.; Dolatabadi, N.; Gude, N.; Most, P.; Sussman, M.A.; Hassel, D. Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish. J. Cell Sci. 2012, 125 (Pt 2), 287–294.
Gammons, J.; Trebak, M.; Mancarella, S. Cardiac-specific deletion of Orai3 leads to severe dilated cardiomyopathy and heart failure in mice. J. Am. Heart Assoc. 2021, 10, e019486.
Zhang, W.; Halligan, K.E.; Zhang, X.; Bisaillon, J.M.; Gonzalez-Cobos, J.C.; Motiani, R.K.; Hu, G.; Vincent, P.A.; Zhou, J.; Barroso, M.; et al. Orai1-mediated I (CRAC) is essential for neointima formation after vascular injury. Circ. Res. 2011, 109, 534–542.
González-Cobos, J.C.; Zhang, X.; Zhang, W.; Ruhle, B.; Motiani, R.K.; Schindl, R.; Muik, M.; Spinelli, A.M.; Bisaillon, J.M.; Shinde, A.V.; et al. Store-independent Orai1/3 channels activated by intracrine leukotriene C4: Role in neointimal hyperplasia. Circ. Res. 2013, 112, 1013–1025.
Johnson, M.T.; Gudlur, A.; Zhang, X.; Xin, P.; Emrich, S.M.; Yoast, R.E.; Courjaret, R.; Nwokonko, R.M.; Li, W.; Hempel, N.; et al. L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins. Proc. Natl. Acad. Sci. USA 2020, 117, 17369–17380.
Johnson, M.; Trebak, M. ORAI channels in cellular remodeling of cardiorespiratory disease. Cell Calcium 2019, 79, 1–10.
Bai, S.; Wei, Y.; Hou, W.; Yao, Y.; Zhu, J.; Hu, X.; Chen, W.; Du, Y.; He, W.; Shen, B.; et al. Orai-IGFBP3 signaling complex regulates high-glucose exposure-induced increased proliferation, permeability, and migration of human coronary artery endothelial cells. BMJ Open Diabetes Res. Care 2020, 8, e001400.
Li, J.; Cubbon, R.M.; Wilson, L.A.; Amer, M.S.; McKeown, L.; Hou, B.; Majeed, Y.; Tumova, S.; Seymour, V.A.; Taylor, H.; et al. Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation. Circ. Res. 2011, 108, 1190–1198.
Zou, M.; Dong, H.; Meng, X.; Cai, C.; Li, C.; Cai, S.; Xue, Y. Store-operated Ca2+ entry plays a role in HMGB1-induced vascular endothelial cell hyperpermeability. PLoS ONE 2015, 10, e0123432.
Liang, S.J.; Zeng, D.Y.; Mai, X.Y.; Shang, J.Y.; Wu, Q.Q.; Yuan, J.N.; Yu, B.X.; Zhou, P.; Zhang, F.R.; Liu, Y.Y.; et al. Inhibition of Orai1 store-operated calcium channel prevents foam cell formation and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 618–628.
Samanta, K.; Parekh, A.B. Spatial Ca2+ profiling: Decrypting the universal cytosolic Ca2+ oscillation. J. Physiol. 2017, 595, 3053–3062.
Feldman, C.H.; Grotegut, C.A.; Rosenberg, P.B. The role of STIM1 and SOCE in smooth muscle contractility. Cell Calcium 2017, 63, 60–65.
Fahrner, M.; Grabmayr, H.; Romanin, C. Mechanism of STIM activation. Curr. Opin. Physiol. 2020, 17, 74–79.
Soboloff, J.; Rothberg, B.S.; Madesh, M.; Gill, D.L. STIM proteins: Dynamic calcium signal transducers. Nat. Rev. Mol. Cell Biol. 2012, 13, 549–565.
Yu, F.; Sun, L.; Hubrack, S.; Selvaraj, S.; Machaca, K. Intramolecular shielding maintains the ER Ca²⁺ sensor STIM1 in an inactive conformation. J. Cell Sci. 2013, 126 Pt 11, 2401–2410.
Brandman, O.; Liou, J.; Park, W.S.; Meyer, T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 2007, 131, 1327–1339.
Grabmayr, H.; Romanin, C.; Fahrner, M. STIM proteins: An ever-expanding family. Int. J. Mol. Sci. 2020, 22, 378.
Parks, C.; Alam, M.A.; Sullivan, R.; Mancarella, S. STIM1-dependent Ca2+ microdomains are required for myofilament remodeling and signaling in the heart. Sci. Rep. 2016, 6, 25372.
Gilio, K.; van Kruchten, R.; Braun, A.; Berna-Erro, A.; Feijge, M.A.; Stegner, D.; van der Meijden, P.E.; Kuijpers, M.J.; Varga-Szabo, D.; Heemskerk, J.W.; et al. Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation. J. Biol. Chem. 2010, 285, 23629–23638.
Fang, M.; Li, Y.; Wu, Y.; Ning, Z.; Wang, X.; Li, X. miR-185 silencing promotes the progression of atherosclerosis via targeting stromal interaction molecule 1. Cell Cycle 2019, 18, 682–695.
Mao, Y.Y.; Wang, J.Q.; Guo, X.X.; Bi, Y.; Wang, C.X. Circ-SATB2 upregulates STIM1 expression and regulates vascular smooth muscle cell proliferation and differentiation through miR-939. Biochem. Biophys. Res. Commun. 2018, 505, 119–125.
Berna-Erro, A.; Jardin, I.; Salido, G.M.; Rosado, J.A. Role of STIM2 in cell function and physiopathology. J. Physiol. 2017, 595, 3111–3128.
Fernandez, R.A.; Wan, J.; Song, S.; Smith, K.A.; Gu, Y.; Tauseef, M.; Tang, H.; Makino, A.; Mehta, D.; Yuan, J.X. Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am. J. Physiol. Cell Physiol. 2015, 308, C581–C593.
Zhang, X.; Huang, R.; Zhou, Y.; Zhou, W.; Zeng, X. IP3R channels in male reproduction. Int. J. Mol. Sci. 2020, 21, 9179.
Serysheva, I.I. Toward a high-resolution structure of IP₃R channel. Cell Calcium 2014, 56, 125–132.
Lin, Q.; Zhao, G.; Fang, X.; Peng, X.; Tang, H.; Wang, H.; Jing, R.; Liu, J.; Lederer, W.J.; Chen, J.; et al. IP(3) receptors regulate vascular smooth muscle contractility and hypertension. JCI Insight 2016, 1, e89402.
Sampieri, A.; Santoyo, K.; Asanov, A.; Vaca, L. Association of the IP3R to STIM1 provides a reduced intraluminal calcium microenvironment, resulting in enhanced store-operated calcium entry. Sci. Rep. 2018, 8, 13252.
Boulay, G.; Brown, D.M.; Qin, N.; Jiang, M.; Dietrich, A.; Zhu, M.X.; Chen, Z.; Birnbaumer, M.; Mikoshiba, K.; Birnbaumer, L. Modulation of Ca2+ entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): Evidence for roles of TRP and IP3R in store depletion-activated Ca2+ entry. Proc. Natl. Acad. Sci. USA 1999, 96, 14955–14960.
Hamada, K.; Mikoshiba, K. IP(3) receptor plasticity underlying diverse functions. Annu. Rev. Physiol. 2020, 82, 151–176.
Bartok, A.; Weaver, D.; Golenár, T.; Nichtova, Z.; Katona, M.; Bánsághi, S.; Alzayady, K.J.; Thomas, V.K.; Ando, H.; Mikoshiba, K.; et al. IP(3) receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer. Nat. Commun. 2019, 10, 3726.
Szabadkai, G.; Bianchi, K.; Várnai, P.; De Stefani, D.; Wieckowski, M.R.; Cavagna, D.; Nagy, A.I.; Balla, T.; Rizzuto, R. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. 2006, 175, 901–911.
Narayanan, D.; Adebiyi, A.; Jaggar, J.H. Inositol trisphosphate receptors in smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H2190–H2210.
Luo, X.; Li, W.; Künzel, K.; Henze, S.; Cyganek, L.; Strano, A.; Poetsch, M.S.; Schubert, M.; Guan, K. IP3R-mediated compensatory mechanism for calcium handling in human induced pluripotent stem cell-derived cardiomyocytes with cardiac ryanodine receptor deficiency. Front. Cell Dev. Biol. 2020, 8, 772.
Stokke, M.K.; Rivelsrud, F.; Sjaastad, I.; Sejersted, O.M.; Swift, F. From global to local: A new understanding of cardiac electromechanical coupling. Tidsskr. Nor. Laegeforen. Tidsskr. Prakt. Med. Raekke 2012, 132, 1457–1460.
Xiao, J.; Liang, D.; Zhao, H.; Liu, Y.; Zhang, H.; Lu, X.; Liu, Y.; Li, J.; Peng, L.; Chen, Y.H. 2-Aminoethoxydiphenyl borate, a inositol 1,4,5-triphosphate receptor inhibitor, prevents atrial fibrillation. Exp. Biol. Med. 2010, 235, 862–868.
Periasamy, M.; Kalyanasundaram, A. SERCA pump isoforms: Their role in calcium transport and disease. Muscle Nerve 2007, 35, 430–442.
Rahate, K.; Bhatt, L.K.; Prabhavalkar, K.S. SERCA stimulation: A potential approach in therapeutics. Chem. Biol. Drug Des. 2020, 95, 5–15.
Shaikh, S.A.; Sahoo, S.K.; Periasamy, M. Phospholamban and sarcolipin: Are they functionally redundant or distinct regulators of the Sarco(Endo)Plasmic Reticulum Calcium ATPase? J. Mol. Cell. Cardiol. 2016, 91, 81–91.
Periasamy, M.; Bhupathy, P.; Babu, G.J. Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc. Res. 2008, 77, 265–273.
Lipskaia, L.; Keuylian, Z.; Blirando, K.; Mougenot, N.; Jacquet, A.; Rouxel, C.; Sghairi, H.; Elaib, Z.; Blaise, R.; Adnot, S.; et al. Expression of sarco (endo) plasmic reticulum calcium ATPase (SERCA) system in normal mouse cardiovascular tissues, heart failure and atherosclerosis. Biochim. Biophys. Acta 2014, 1843, 2705–2718.
Dupont, S.; Maizel, J.; Mentaverri, R.; Chillon, J.M.; Six, I.; Giummelly, P.; Brazier, M.; Choukroun, G.; Tribouilloy, C.; Massy, Z.A.; et al. The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension. Am. J. Physiol. Heart Circ. Physiol. 2012, 302, H1524–H1532.
Fernandez-Tenorio, M.; Niggli, E. Stabilization of Ca2+ signaling in cardiac muscle by stimulation of SERCA. J. Mol. Cell. Cardiol. 2018, 119, 87–95.
Torre, E.; Lodrini, A.; Barassi, P.; Ferrandi, M.; Boz, E.; Bussadori, C.; Ferrari, P.; Bianchi, G.; Rocchetti, M. Istaroxime improves diabetic diastolic dysfunction through SERCA stimulation. Arch. Cardiovasc. Dis. Suppl. 2019, 11, 234–235.
Adachi, T.; Weisbrod, R.M.; Pimentel, D.R.; Ying, J.; Sharov, V.S.; Schöneich, C.; Cohen, R.A. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat. Med. 2004, 10, 1200–1207.
Tong, X.; Ying, J.; Pimentel, D.R.; Trucillo, M.; Adachi, T.; Cohen, R.A. High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration. J. Mol. Cell. Cardiol. 2008, 44, 361–369.
Qin, F.; Siwik, D.A.; Lancel, S.; Zhang, J.; Kuster, G.M.; Luptak, I.; Wang, L.; Tong, X.; Kang, Y.J.; Cohen, R.A.; et al. Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. J. Am. Heart Assoc. 2013, 2, e000184.
Ying, J.; Sharov, V.; Xu, S.; Jiang, B.; Gerrity, R.; Schoneich, C.; Cohen, R.A. Cysteine-674 oxidation and degradation of sarcoplasmic reticulum Ca2+ ATPase in diabetic pig aorta. Free Radic. Biol. Med. 2008, 45, 756–762.
Liu, G.; Wu, F.; Jiang, X.; Que, Y.; Qin, Z.; Hu, P.; Lee, K.S.S.; Yang, J.; Zeng, C.; Hammock, B.D.; et al. Inactivation of Cys(674) in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase. Br. J. Pharmacol. 2020, 177, 1793–1805.
Thompson, M.D.; Mei, Y.; Weisbrod, R.M.; Silver, M.; Shukla, P.C.; Bolotina, V.M.; Cohen, R.A.; Tong, X. Glutathione adducts on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic function as well as promote ischemic blood flow recovery. J. Biol. Chem. 2014, 289, 19907–19916.
Mei, Y.; Thompson, M.D.; Shiraishi, Y.; Cohen, R.A.; Tong, X. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase C674 promotes ischemia- and hypoxia-induced angiogenesis via coordinated endothelial cell and macrophage function. J. Mol. Cell. Cardiol. 2014, 76, 275–282.
Que, Y.; Shu, X.; Wang, L.; Hu, P.; Wang, S.; Xiong, R.; Liu, J.; Chen, H.; Tong, X. Inactivation of cysteine 674 in the SERCA2 accelerates experimental aortic aneurysm. J. Mol. Cell. Cardiol. 2020, 139, 213–224.
Goodman, J.B.; Qin, F.; Morgan, R.J.; Chambers, J.M.; Croteau, D.; Siwik, D.A.; Hobai, I.; Panagia, M.; Luptak, I.; Bachschmid, M.; et al. Redox-resistant SERCA attenuates oxidant-stimulated mitochondrial calcium and apoptosis in cardiac myocytes and pressure overload-induced myocardial failure in mice. Circulation 2020, 142, 2459–2469.
SERCA. Available online: https://clinicaltrials.gov/ct2/show/NCT01643330?term=SERCA&draw=2&rank=5 (accessed on 12 August 2021).
SERCA. Available online: https://clinicaltrials.gov/ct2/show/NCT01966887?term=SERCA&draw=2&rank=2 (accessed on 12 August 2021).
SERCA. Available online: https://clinicaltrials.gov/ct2/show/NCT00534703?term=SERCA&draw=2&rank=1 (accessed on 12 August 2021).
SERCA. Available online: https://clinicaltrials.gov/ct2/show/NCT04703842?term=SERCA&draw=2&rank=4 (accessed on 12 August 2021).
SERCA. Available online: https://clinicaltrials.gov/ct2/show/NCT02772068?term=SERCA&draw=2&rank=3 (accessed on 12 August 2021).
George, M.; Rajaram, M.; Shanmugam, E.; VijayaKumar, T.M. Novel drug targets in clinical development for heart failure. Eur. J. Clin. Pharmacol. 2014, 70, 765–774.
Na+/Ca2+ Exchanger. Available online: https://clinicaltrials.gov/ct2/show/NCT00534703?term=Na%2B%2FCa2%2B+exchanger&draw=2&rank=1 (accessed on 12 August 2021).

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Allergy

Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

XiaoYong Tong

View Times: 469

Update Date: 08 Oct 2021

Table of Contents

Video Upload Options

Confirm

1. Introduction