British journal of pharmacology · 2025
A potential therapeutic target at Connexin 43 serine phosphorylation against ischaemia/reperfusion arrhythmia.
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Fu Zhiping, Li Shuanglei, Xue Jingyi, Li Qiang, Jiang Tianhui, Wu Lulin, Wang Luqi, Zhang Hanying, Geng Xin, Guo Xintong, Yan Xinxin, You Hongjie, Zhang Lingxi, Zhang Yimeng, Song Tao, Wu Yongquan, Yu Xiaofeng, Hou Yunlong, Luo Dali
Аннотация
BACKGROUND AND PURPOSE: Dephosphorylation of several phosphor residues in connexin 43 (Cx43) is critically involved in ischaemia/reperfusion (I/R) arrhythmias. Here, we sought to identify constitutive Cx43-serine 282 (S282) dephosphorylation as an independent and targetable substrate to delineate reperfusion arrhythmogenesis.
EXPERIMENTAL APPROACH: Reperfusion arrhythmias were induced by rat I/R (15/45 min), identified in heterozygous knock-in mice with S282 to alanine (Cx43-S282A/+) and rescued by LB100, a specific protein phosphatase 2A (PP2A) inhibitor, via surface electrocardiogram and epicardial mapping detections. TAT-HA-L2, a mimic of Cx43-cytoplasmic-loop domain (L2), was assessed in mitigating Cx43-S282 dephosphorylation-associated arrhythmogenicity.
KEY RESULTS: Upon I/R, rats exeperienced myocardium injury, ventricular tachycardia/fibrillation, increased PP2A activity and Cx43-S282 hypophosphorylation, whereas Cx43-S282A/+ mice had spontaneous ventricular arrhythmias with normal cardiac function/morphology. LB100 significantly attenuated these arrhythmias by restoring PP2A-C and Cx43-S282 phosphorylation. Slow and irregular electrical conduction, premature Ca2+ transients and afterdepolarisations were found and normalised by LB100, or Gap19 peptide treatment (Cx43 hemichannel inhibitor), in Cx43-S282A/+ ventricles. Mechanistically, serine 282 locates within SH3-binding domain of the Cx43-carboxyl-terminus. TAT-HA-L2 bound with Cx43-S282 dephosphorylated proteins in S282A-expressed 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.
CONCLUSIONS AND IMPLICATIONS: Cx43-S282 dephosphorylation can trigger reperfusion arrhythmias by impairing gap junction intercellular communication while favouring hemichannel permeability. An up-regulated intramolecular interaction between L2 and Cx43-carboxyl-terminus is associated with this arrhythmogenicity, providing a novel and targetable mechanism to preserve the heart from ischaemia/reperfusion arrhythmias.
EXPERIMENTAL APPROACH: Reperfusion arrhythmias were induced by rat I/R (15/45 min), identified in heterozygous knock-in mice with S282 to alanine (Cx43-S282A/+) and rescued by LB100, a specific protein phosphatase 2A (PP2A) inhibitor, via surface electrocardiogram and epicardial mapping detections. TAT-HA-L2, a mimic of Cx43-cytoplasmic-loop domain (L2), was assessed in mitigating Cx43-S282 dephosphorylation-associated arrhythmogenicity.
KEY RESULTS: Upon I/R, rats exeperienced myocardium injury, ventricular tachycardia/fibrillation, increased PP2A activity and Cx43-S282 hypophosphorylation, whereas Cx43-S282A/+ mice had spontaneous ventricular arrhythmias with normal cardiac function/morphology. LB100 significantly attenuated these arrhythmias by restoring PP2A-C and Cx43-S282 phosphorylation. Slow and irregular electrical conduction, premature Ca2+ transients and afterdepolarisations were found and normalised by LB100, or Gap19 peptide treatment (Cx43 hemichannel inhibitor), in Cx43-S282A/+ ventricles. Mechanistically, serine 282 locates within SH3-binding domain of the Cx43-carboxyl-terminus. TAT-HA-L2 bound with Cx43-S282 dephosphorylated proteins in S282A-expressed 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.
CONCLUSIONS AND IMPLICATIONS: Cx43-S282 dephosphorylation can trigger reperfusion arrhythmias by impairing gap junction intercellular communication while favouring hemichannel permeability. An up-regulated intramolecular interaction between L2 and Cx43-carboxyl-terminus is associated with this arrhythmogenicity, providing a novel and targetable mechanism to preserve the heart from ischaemia/reperfusion arrhythmias.