Charting novel aspects of the cardiac sodium channel

Each heartbeat is driven by electrical activity moving through the heart which results in contraction of the heart. Ion channels generate his electrical activity. This dissertation is focussed on one of these ion channels: the cardiac sodium channel Na_V1.5. This channel is responsible for the generation of sodium current, which drives the fast upstroke of action potentials and is therefore vital for the propagation of electrical signals through the heart. Dysfunction of Na_V1.5 can occur because of mutations in SCN5A, which is the gene encoding Na_V1.5, or secondary to heart failure and/or myocardial infarction. Dysfunctional Na_V1.5 and consequent sodium current abnormalities can lead to severe arrhythmias as well as sudden cardiac death.
Part I of this dissertation focusses on the role of Na_V1.5 in atrial and atrio-ventricular conduction. Here, we provide evidence that Na_V1.5 function differs in the various stage of atrial fibrillation, and that disrupted calcium homeostasis secondary to Na_V1.5 dysfunction leads to disrupted atrio-ventricular conduction.
In Part II attention is shifted to the impact of Na_V1.5 on structural properties of the heart. We demonstrate that Na_V1.5 is crucial for the development of the heart during early embryonic stages through non-electrogenic effects, and demonstrate the impact of genetic modifiers and increasing age on disease severity secondary to Na_V1.5 dysfunction.
Finally, Part III focusses on the regulation of specific localisation of Na_V1.5 in cardiomyocytes. We demonstrate that low levels of dystrophin expression is sufficient for proper Na_V1.5 function, and unravel that microtubule plus-end tracking proteins (+TIPs) are involved in targeted trafficking of Na_V1.5. In addition, we provide an overview of interactions between Na_V1.5 interacting proteins and +TIPs, and propose that these interactions are vital for the specific localisation pattern of Na_V1.5 in cardiomyocytes.