Lay summary
Sudden death caused by disturbances of the cardiac rhythm (arrhythmias) is frequent in industrialized countries. The mechanisms underlying cardiac arrhythmias are complex and dynamic. Thus far, we only partially understand the molecular and cellular mechanisms involved in this type of diseases. The general goal of this project is to obtain detailed information about the regulation of a specific ion channel (a membrane protein mediating the flow of ions across the cell membrane) called Nav1.5. This channel is mainly expressed in the heart and mediates the influx of sodium ions into the cardiac cells, hence playing a key role in the electrical activity of the heart. Many recent studies have demonstrated that malfunction of this channel caused by genetic mutations may lead to a large number of different cardiac diseases. In this project, we postulate that this channel is regulated by two types of proteins interacting directly with it: (1) ubiquitin ligases and (2) anchoring proteins.In order to study the physiological relevance of these interactions, in this project, we plan to generate mouse lines that will be genetically modified. We will alter the domains of the mouse gene coding for Nav1.5 in a way that these proteins will not be able to interact with the channel anymore. Afterwards, we will investigate the consequences of these genetic modifications on the electrical activity of the heart. This will be performed by carrying out biochemistry, cellular and whole-animal experiments. The new knowledge that will be obtained by performing the proposed experiments will allow us to understand much more precisely how Nav1.5 is regulated. This will permit us to propose new models about how this channel is involved in arrhythmic diseases and eventually better prevent sudden cardiac death.