Remodeled Connexin 43 hemichannels alter cardiac excitability and promote arrhythmias

Abstract

Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of a dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pre-treatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability and greater plasma membrane depolarization, which subsequently leads to triggered activity. These cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac stress-induced arrhythmogenicity.

Brugada Phenotype Following a Cocaine Overdose

“…These changes in Cx-43 profiles, particularly the increased localization of dephosphorylated Cx-43 in regions adjacent to CBN, may disrupt the normal propagation of electrical signals in the heart [ 7 ]. Since Brugada syndrome manifests as ventricular arrhythmias and is frequently associated with ECG patterns resembling right bundle branch block, alterations in connexin function could significantly contribute to the arrhythmogenic setting observed in this syndrome and contribute to the ventricular arrhythmias found [ 9 ].…”

Structural basis of connexin-36 gap junction channel inhibition

“…Different GJCs also take an active role in cell growth and differentiation, tissue development and homeostasis 11 , and disruptions of connexin function can lead to severe pathological conditions. For example, dysfunctions in different connexin channels have been linked to deafness (Cx26) 12 , cataracts (Cx46 and Cx50) 13 , peripheral neuropathy (X-linked Charcot-Marie-Tooth disease, Cx32) 14 , cardiac arrhythmias (Cx40 and Cx43) 15,16 and various forms of cancer 17 .…”