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    • Cx is a phosphoprotein that is predominantly phosphorylated

    2021-10-23

    Cx43 is a phosphoprotein that is predominantly phosphorylated in the control state. Cx43 can be phosphorylated by a number of kinases and dephosphorylated by protein phosphatases such as PP1 and PP2A [6], [10]. Posttranslational phosphorylation of Cx43 is thought to influence intercellular coupling through gap junction remodeling, and dysregulation of Cx43 phosphorylation occurs in disease states [8], [11], [12], [28], [29], [42], [47], [48], [49]. Cx43 can be phosphorylated at at least 17 serine sites and two tyrosine sites located at the C-terminus via several kinases, including protein kinase A (PKA), protein kinase C (PKC), casein kinase 1 (CK1), mitogen-activated protein kinase (MAPK), Ca/calmodulin-dependent protein kinase II (CaMKII), and Src kinases (Fig. 1) [12], [28], [29], [46], [49], [50]. The level of kinase activation and related Cx43 jtc motors and phosphorylation affects gap junctional conductance. PKA activation, in particular, has been shown to increase conductance and improve cell-to-cell communication [51], whereas increased activation of PKC decreases gap junctional communication [52]. Phosphorylation by CK1, MAPK, and Src kinases appears to influence intercellular communication by promoting Cx43 localization and gap junction assembly [50]. Emerging evidence suggests that dephosphorylation of Cx43, in opposition to this kinase activity, leads to reduced gap junctional communication and increased arrhythmic susceptibility [8], [12], [29], [41], [42], [47], [48]. Dephosphorylation of Cx43 (by phosphatases) has been shown to decrease gap junctional communication, whether assessed in neonatal rat ventricular cell pairs with activation of endogenous phosphatases [9], or in perfused whole rat hearts during myocardial ischemia [40], [41]. We found a 64% increase in nonphosphorylated Cx43 in HF rabbits compared to controls (in which Cx43 was primarily phosphorylated) [8]. Dephosphorylation of Cx43 has also been shown to occur in models of ischemia, and is associated with reduced gap junctional communication, slow conduction, and increased arrhythmogenicity [8], [40], [41], [42], [53]. Thus, connexin phosphorylation and dephosphorylation play an important role in regulating gap junction channel function and the development of cardiac arrhythmias in diseased hearts. Findings on the effects of Cx43 phosphorylation at specific amino acid sites (primarily serine sites) have been contradictory. Prolonged ischemia, electrical uncoupling, and slow conduction have been associated with Cx43 dephosphorylation at Ser306 [54], [55], Ser297 [54], Ser365 [56], [57] and Ser368 [41], [54], while phosphorylation at Ser279 and Ser282 has also been correlated with decreased conduction and dye coupling [58], [59]. Phosphorylation by PKC, which may phosphorylate Ser365, Ser368, Ser369, Ser372, and Ser373 [60], has been associated with increased macroscopic electrical coupling [61], but has also been associated with reduced single channel conductance and a decrease in dye coupling [52], [61]. Moreover, studies on the interactions between Cx43 phosphorylation sites have also found conflicting results. PKA phosphorylation at Ser364 and/or Ser365 has been found to enhance phosphorylation [60], yet other studies have found that dephosphorylation of Ser365 is necessary for PKC-induced phosphorylation of Ser368 [56], [57], [62]. Decreased conduction, gap junction channel closure, and associated arrhythmias have also been linked to increased tyrosine phosphorylation of Cx43 [21], [32], [33], [63], [64], particularly phosphorylation of Tyr265 [65], [66], [67]. These findings, many of which seem contradictory, emphasize the complex role of Cx43 phosphorylation in the regulation of gap junctions. Though not as prevalent or extensively studied, Cx40 and Cx45 may also play a role in cardiac gap junctional communication. Like Cx43, Cx40 is regulated by posttranslational phosphorylation [68], [69], and may be phosphorylated by PKA and PKC [69]. Cx40 phosphorylation by PKA in SKHep1 cells resulted in increased gap junction conductance and metabolic coupling [69]. Decreased Cx40 phosphorylation in microvascular endothelial cells, both during sepsis and with PKA inhibition, has been associated with decreased electrical coupling, which can be prevented by PKA activation [70]. Taken together, these studies suggest that Cx40 phosphorylation state may influence gap junctional conduction and could play a role in atrial arrhythmias. Indeed, recent studies have started to investigate the role of Cx40 in atrial fibrillation, and have found multiple Cx40 mutations associated with altered conduction properties [71], [72], [73], [74], [75], [76]. The relationship between these mutations, altered conduction, and connexin phosphorylation remains to be explored.