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Here, we sought to identify constitutive Cx43\u2010serine 282 (S282) dephosphorylation as an independent and targetable substrate to delineate reperfusion arrhythmogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Reperfusion arrhythmias were induced by rat I\/R (15\/45\u2009min), identified in heterozygous knock\u2010in mice with S282 to alanine (Cx43\u2010S282A\/+) and rescued by LB100, a specific protein phosphatase 2A (PP2A) inhibitor, via surface electrocardiogram and epicardial mapping detections. TAT\u2010HA\u2010L2, a mimic of Cx43\u2010cytoplasmic\u2010loop domain (L2), was assessed in mitigating Cx43\u2010S282 dephosphorylation\u2010associated arrhythmogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Upon I\/R, rats exeperienced myocardium injury, ventricular tachycardia\/fibrillation, increased PP2A activity and Cx43\u2010S282 hypophosphorylation, whereas Cx43\u2010S282A\/+ mice had spontaneous ventricular arrhythmias with normal cardiac function\/morphology. LB100 significantly attenuated these arrhythmias by restoring PP2A\u2010C and Cx43\u2010S282 phosphorylation. Slow and irregular electrical conduction, premature Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transients and afterdepolarisations were found and normalised by LB100, or Gap19 peptide treatment (Cx43 hemichannel inhibitor), in Cx43\u2010S282A\/+ ventricles. Mechanistically, serine 282 locates within SH3\u2010binding domain of the Cx43\u2010carboxyl\u2010terminus. TAT\u2010HA\u2010L2 bound with Cx43\u2010S282 dephosphorylated proteins in S282A\u2010expressed HeLa cells, as well as in S282A\/+ and I\/R isolated cardiomyocytes, more than in their counterpart controls. LB100 can prevent their enhanced binding and ATP release because of S282 dephosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Cx43\u2010S282 dephosphorylation can trigger reperfusion arrhythmias by impairing gap junction intercellular communication while favouring hemichannel permeability. An up\u2010regulated intramolecular interaction between L2 and Cx43\u2010carboxyl\u2010terminus is associated with this arrhythmogenicity, providing a novel and targetable mechanism to preserve the heart from ischaemia\/reperfusion arrhythmias.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70090","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T10:54:47Z","timestamp":1749725687000},"page":"4516-4534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A potential therapeutic target at Connexin 43 serine phosphorylation against ischaemia\/reperfusion arrhythmia"],"prefix":"10.1111","volume":"182","author":[{"given":"Zhiping","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Metabolic Disturbance Related Cardiovascular Disease Capital Medical University  Beijing 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