Enhanced activation of p21-activated kinase 1 in heart failure contributes to dephosphorylation of connexin 43

Ai, Xun; Jiang, Aiyang; Ke, Yunbo; Solaro, R. John; Pogwizd, Steven M.

doi:10.1093/cvr/cvr163

Cited by 41 publications

(40 citation statements)

References 42 publications

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“…The phosphorylation of Cx43 at different sites and by different kinases may have different effects. Phosphorylation of Cx43 at serine 279/282 results in impaired cell communication (15), while enhanced dephosphorylation of Cx43 contributes to slow conduction in heart failure via increased activation of p21-activated kinase 1 (16). In addition, the phosphorylation status of Cx43 also affects its suppressive effect on cell proliferation (17).…”

Section: Discussionmentioning

confidence: 99%

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Huang

Wei

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. Mitochondrial connexin 43 (Cx43) is important in cardioprotection by ischemic preconditioning; however, whether mitochondrial Cx43 is involved in mitochondrial dysfunction in the pathogenesis of dilated cardiomyopathy (DCM) remains to be elucidated. The present study was performed to investigate the changes in expression and the phosphorylation state of mitochondrial Cx43 in a rat model of DCM, and to determine whether the altered phosphorylation state of mitochondrial Cx43 was involved in mitochondrial dysfunction. A rat model of DCM was generated by daily oral administration of furazolidone (FZD) for 30 weeks. Reverse transcription polymerase chain reaction and western blot analysis revealed a decrease in the overall expression of Cx43, accompanied by reduced levels of serine 368-phosphorylated-Cx43 immunoreactivity in the myocardium and myocardial mitochondria. In addition, the mitochondrial membrane potential and the activities of cytochrome c oxidase, succinate dehydrogenase and protein kinase C (PKC) ε were all significantly reduced compared with those of the control group. Phorbol-12-myristate-13-acetate (PMA), a specific PKC activator, partially reversed the FZD-induced mitochondrial Cx43 dephosphorylation at serine 368 and mitochondrial dysfunction in the cardiomyocytes. However, pretreatment with 18β-glycerrhetinic acid, a connexin channel inhibitor, eliminated the mitochondrial protective effect of PMA in the cardiomyocytes sparsely plated without cell to cell contact. These results suggested that dephosphorylation of mitochondrial Cx43 at serine 368, due to the suppression of PKCε activity, may be a novel mechanism for mitochondrial dysfunction in the pathogenesis of DCM.

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Section: Discussionmentioning

confidence: 99%

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Huang

Wei

Zhang

et al. 2015

Molecular Medicine Reports

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“…Connexin 43 is suggested to be regulated by both PP1 and PP2A based on the phosphorylation sites on connexin 43, the localization of the protein phosphatases to the myocyte intercalated disc, and evidence supporting reduced gap junction communication linked with increased phosphatase activity [51,52]. As further support of this regulation, PP2A is required for the dephosphorylation of connexin 43 at serine 368 in a pituitary cell line [53].…”

Section: Cardiac Pp2a Regulatory Targetsmentioning

confidence: 99%

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Lubbers

Mohler

2016

Journal of Molecular and Cellular Cardiology

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Reversible protein phosphorylation is central to a variety of cardiac processes including excitation-contraction coupling, Ca2+ handling, cell metabolism, myofilament regulation, and cell-cell communication. While kinase pathways linked with elevated adrenergic signaling have been a major focus for the cardiovascular field over the past half century, new findings support the critical role of protein phosphatases in both health and disease. Protein phosphatase 2A (PP2A) is a central cardiac phosphatase that regulates diverse myocyte functions through a host of target molecules. Notably, multiple mechanisms have evolved to dynamically tune PP2A function, including modulation of the composition, phosphorylation, methylation, and localization of PP2A holoenzyme populations. Further, aberrations in this regulation of PP2A function may contribute to cardiac pathophysiology. In summary, PP2A is a critical regulatory molecule in both health and disease, with a myriad of targets in heart. Based on their unique structure, localization, and regulatory properties, PP2A subunits represent exciting therapeutic targets to modulate altered adrenergic signaling in cardiovascular disease.

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“…In myocytes, PP2A activity is linked with multiple targets important in membrane excitability and excitation-contraction coupling including the ryanodine receptor (RyR2), connexin43, Ca v 1.2, troponin, Na ϩ /Ca 2ϩ exchanger (NCX), and phospholamban (16 -22). Although manipulation of PP2A activity or expression in animal or cell models produces defects in myocyte physiology and cardiac phenotypes (19,20,(23)(24)(25)(26), the role and regulation of this critical enzyme family in cardiovascular disease is still largely elusive. In fact, we lack even a basic fundamental understanding of the expression, activity, and regulation of protein phosphatases in heart and/or in cardiovascular disease.…”

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confidence: 99%

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

DeGrande

Little

Nixon

et al. 2013

Journal of Biological Chemistry

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Background: PP2A regulates cardiac excitability and physiology. Results: PP2A regulation in heart occurs through integrative transcriptional, translational, and post-translational control of three classes of subunits (17 genes) to control holoenzyme synthesis, localization, and maintenance; pathways are mechanistically altered in heart disease. Conclusion:Multiple mechanisms are present for acute and chronic regulation of specific PP2A populations. Significance: Results provide molecular insight into cardiac PP2A regulation.

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Enhanced activation of p21-activated kinase 1 in heart failure contributes to dephosphorylation of connexin 43

Abstract: PAK1 and PP2A are integral components of a macromolecular complex with cardiac Cx43, and increased activation of associated PAK1 can contribute to enhanced Cx43 dephosphorylation and impaired intercellular coupling that may underlie slow conduction in HF.

Cited by 41 publications

References 42 publications

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

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