Novel approaches to target sodium channel trafficking in cardiomyocytes

The cardiac sodium channel Naᵥ1.5, encoded by the SCN5A gene, plays a crucial role in the electrical activity of the heart. Naᵥ1.5 dysfunction can disrupt this process, leading to arrhythmias and sudden cardiac death. Current pharmacological treatments are limited and restoring Naᵥ1.5 function remains a challenge. We investigated new potential strategies aimed at restoring Naᵥ1.5 dysfunction. In particular, the thesis investigates trafficking pathways as novel therapeutic targets, while exploring their remodeling in the setting of pathological conditions as well as their modulatory effect on Naᵥ1.5 subcellular (re)distribution.
Part I focuses on the therapeutic potential of mexiletine in inherited primary electrical disorders. We demonstrated, for the first time in a human model of SCN5A overlap syndrome, the beneficial effects of chronic treatment with therapeutic concentrations of mexiletine. Mechanistically, we confirmed that chronic mexiletine can increase sodium current (I_Na) by enhancing Naᵥ1.5 membrane localization, in line with its proposed mechanism as a pharmacological chaperone.
Part II focuses on inherited disorders affecting Naᵥ1.5-interacting proteins associated with reduced I_Na, assessing the therapeutic potential of modulating MT dynamics. Using mouse models of Duchenne muscular dystrophy and arrhythmogenic cardiomyopathy we studied the impact of reducing MT detyrosination on the (re)distribution of Naᵥ1.5 clusters within the subcellular domains of CMs and showed its beneficial effects on I_Na density. Overall, findings presented in this thesis have unravelled (part of) the intricate mechanisms involved in Naᵥ1.5 trafficking and offer exciting prospects for future development of targeted therapies aimed at preventing arrhythmias and sudden cardiac death.