In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5

Sudden death caused by disturbances of the cardiac rhythm (arrhythmias) is a common cause of death in industrialized countries. The mechanisms underlying cardiac arrhythmias are complex and dynamic. Thus far, we only partially understand the molecular and cellular mechanisms underlying these diseases. The general goal of this project is to obtain detailed information about the regulation of one 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 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 pathologies. 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, we have generated mouse lines that have been genetically modified. Important domains of the mouse gene coding for Nav1.5 have been altered in a way that these proteins will not be able anymore to interact with the channel. We are currently investigating the consequences of these genetic modifications on the electrical activity of the heart. to this end, we are 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.