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    • The most ubiquitous serine threonine phosphatases such as

    2022-07-01

    The most ubiquitous serine/threonine phosphatases, such as PP1, PP2A, and PP2B are known to contribute to the majority of phosphatase activity in the heart [4]. Dysregulation of these and other PPs have been found in numerous CVDs, including heart failure (HF), and may play a critical role in reduced intercellular coupling and arrhythmia development via connexin protein dephosphorylation [8], [9], [10]. Gap junctional channels, composed of connexins, are specialized membrane structures. These gap junction channels critically influence electrical and chemical signal propagation throughout the heart [20], [21]. Conduction slowing arises from decreased depolarizing currents and/or decreased gap junctional coupling, which could underlie reentry occurring in various arrhythmias, such as during the transition from ventricular tachycardia to the fatal cardiac arrhythmia ventricular fibrillation [22], [23], [24], [25] or during atrial fibrillation induction and/or maintenance in acute ischemia or HF [26], [27]. Thus, the following review explores the importance of protein phosphatase regulation in connexin phosphorylation states, the impact of dysregulation in HF and altered conduction, and the implications for protein phosphatases as therapeutic targets.
    Cardiac connexin dysregulation Cell-to-cell electrical coupling in the heart occurs mainly via gap junctions. These membrane structures consist of intercellular hemichannels formed from an assembly of connexins that connect adjacent cells and allow for electrical and chemical communication. Connexins are four-pass transmembrane proteins with two extracellular loops (EL), one cytosolic loop, and both the N-terminus and C-terminus towards the cytosol. Six connexin subunits assemble to form a connexon hemichannel, and interaction between the ELs of adjacent cells combines two hemichannels to form a gap junction channel. In addition to their primary role in hemichannel formation, connexins also interact with scaffolding proteins at the C-terminus, and may play a role in key signaling pathways and S1RA mg regulation [11], [12], [28], [29], [30]. Connexin 43 in particular has been shown to interact with the scaffold protein zonula occludens-1 (ZO-1), which regulates gap junction formation and properties [21], [31], [32], [33], [34], [35]. Thousands of gap junction channels may assemble together to form macromolecular complexes known as gap junction plaques, which facilitate electrical current propagation from cell to cell, enabling coordinated cardiomyocyte contraction. The hemichannels that comprise gap junctions may open or close in response to numerous triggers, including changes in transmembrane potential, changes in intracellular or extracellular ion concentrations, or alterations in phosphorylation status of connexin proteins [11], [12], [28], [29], [30]. Connexin 43 (Cx43) is the major connexin expressed in the ventricles, but is also present in atrial and endothelial cells. Connexin 40 (Cx40) and connexin 45 (Cx45) are also expressed in cardiac tissue, but are predominantly found in the atria [6], [11] and atrioventricular conduction system [36], [37], and are less abundant overall. The relative amounts, composition and distribution of these connexins have been shown to influence the conduction properties of cells [38], [39]. Reduced Cx43 abundance is found in myocardial ischemia and HF. Downregulation of Cx43 expression occurs in myocardial ischemia in rat and rabbit hearts [40], [41], as well as HF models in dog and rabbit, and in failing human hearts [8], [20], [42], [43], [44], [45]. In left ventricular (LV) myocytes isolated from a rabbit model of nonischemic HF (combined aortic insufficiency and aortic constriction), we found that total Cx43 protein was decreased by 34% in HF compared to controls [8]. In further studies conducted in Cx43 knockdown rabbit myocytes with reduced expression but preserved phosphorylation state, we found reduced cell coupling, evaluated by Lucifer Yellow (LY) dye transfer, compared with controls. Cx43 was also overexpressed in HF rabbit myocytes to levels comparable with normal myocytes. Overexpression of Cx43 improved cell coupling in HF myocytes when compared with HF controls [42]. We recently also discovered that downregulated Cx43 also plays an important role in slowing of conduction and enhanced atrial arrhythmogenicity in the aged atrium [46]. These studies, in addition to studies in Cx43 heterozygous knockout mice, support the idea that decreased expression of Cx43 can result in slow conduction and increased susceptibility to cardiac arrhythmias [8], [20], [40], [41], [42], [43], [44], [45], [46], [47], [48].