Lay summary
Sudden death caused by disturbances of thecardiac 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 cellularmechanisms underlying these diseases.The general goal of this project is to obtain detailed information aboutthe regulation of one specific ion channel (a membrane protein mediatingthe flow of ions across the cell membrane) called Nav1.5. This channelis mainly expressed in the heart and mediates the influx of sodium ionsinto cardiac cells, hence playing a key role in the electricalactivity of the heart. Many recent studies have demonstrated thatmalfunction of this channel caused by genetic mutations may lead to alarge number of different cardiac pathologies.In this project, we postulate that this channel is regulated by twotypes of proteins interacting directly with it: (1) ubiquitin ligasesand (2) anchoring proteins.In order to study the physiological relevance of these interactions, we have generated mouse lines that have been geneticallymodified. Important domains of the mouse gene coding for Nav1.5 have been alteredin a way that these proteins will not be able anymore to interact with thechannel. We are currently investigating the consequences ofthese genetic modifications on the electrical activity of the heart. to this end, we are carrying out biochemistry, cellular andwhole-animal experiments.The new knowledge that will be obtained by performing the proposedexperiments will allow us to understand much more precisely how Nav1.5is regulated. This will permit us to propose new models about how thischannel is involved in arrhythmic diseases and eventually better preventsudden cardiac death.