Connexin 43 (Cx43) forms hemichannels (HCs) and gap junction channels (GJCs) in the heart, where their distinct localization and regulation confer divergent functions in heart physiology. HCs are trafficked to the intercalated disc, where they dock to form GJCs that enable direct cell-to-cell communication and facilitate action potential propagation. Although both are composed of the same protein, we aim to define how their roles in cardiac dysfunction are fundamentally different. We previously found that β-adrenergic stimulation increases Cx43 S-nitrosylation in the healthy WT hearts. In knockin mice lacking the Cx43 S-nitrosylation site, Cx43(C271S), Cx43 is primarily expressed as GJCs, not HCs. β-adrenergic stimulation resulted in impaired conduction velocity and contractile performance compared to WT but importantly, did not induce malignant arrhythmias. In pathological models, however, Cx43 remodeling leads to the formation of HCs at the lateral membranes of cardiomyocytes. In MDX mice, which model Duchenne muscular dystrophy, β-adrenergic stimulation promotes the opening of lateralized HCs through direct S-nitrosylation, disrupting membrane excitability and triggering severe arrhythmias and myocardial injury. MDX mice genetically modified to reduce Cx43 S-nitrosylation displayed zero lethal arrhythmias and markedly reduced myocardial injury. Taken together, these models demonstrate that GJCs and HCs make distinct, nonredundant contributions to cardiac dysfunction. Lateralized HC activity drives arrhythmogenesis and myocardial injury, while altered GJC function primarily impacts conduction and contractility. These findings highlight the importance of distinguishing GJC mediated from HC-mediated mechanisms when studying connexin-related diseases or designing targeted therapies.
Quan et al. (Sun,) studied this question.