Connexin43 dephosphorylation at serine 282 is associated with connexin43‐mediated cardiomyocyte apoptosis

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Gap junction protein connexin 43 (Cx43), beyond electrical coordination regulation, plays an important role in the regulation of cardiomyocyte survival, and Cx43 dephosphorylation found in severe cardiac pathologies is proposed to be involved in myocardium injury. However, the mechanisms remain unknown. Here, we found that transfection of adenovirus carrying Cx43 mutant gene at serine 282 substituted with alanine (S282A) into neonatal rat ventricular cardiomyocytes (NRVMs) induced cell apoptosis and Ca2+ transient desynchronization, whereas gap junction inhibitor and knocking down Cx43 expression by Cx43‐miRNA caused uncoupled Ca2+ signalling but no cell death. Similarly, while Cx43‐S282A+/+ failed in generation, Cx43‐S282A+/− mice exhibited cardiomyocyte apoptosis and ventricular arrhythmia in a phosphorylated S282 deficiency‐dependent fashion. Further we found via physical interaction with p38 mitogen‐activated protein kinase (p38 MAPK), S282 dephosphorylation in Cx43 activates p38, factor‐associated suicide and caspase 8 apoptotic pathway. Finally, we found that Cx43 dephosphorylation at S282 participates in ischemia‐reperfusion (IR) induced cardiomyocyte death by activation of p38 MAPK/Fas/FADD/caspase 8. These findings uncover a specific phosphorylation residue of Cx43 in the regulation of cardiomyocyte homeostasis. Deficiency in S282 phosphorylation acts as a trigger inducing cardiomyocyte apoptosis and cardiac arrhythmia, contributing to IR‐induced myocardium apoptosis. Thus, this study provides a potential mechanism for Cx43‐mediated myocardium injury during severe cardiac diseases.Support or Funding InformationThis work was supported by the National Natural Science Foundation (81370339, 81570206) and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201710025023).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.