Objectif
The dynamic modulation of ion channels is crucial to the regulation of cardiac excitability and defects in channel modulation, associated with congenital and acquired cardiac diseases, lead to the development of life threatening arrhythmias. The dynamic modulation of functional expression of ion channels is achieved through changes in cell surface expression and/or functioning of pore-forming channel subunits. Some of the mechanisms used to achieve these regulations involve interactions of pore-forming channel subunits with accessory subunits and post-translational modifications (PTM) of channel components. The voltage-gated Na+ (Nav) current (INa), generated by Nav1.5 channels, is a key regulator of cardiac excitability, modulating action potential waveforms, refractoriness and propagation. Previous studies have linked family mutations in genes encoding Nav1.5 and Nav1.5 interacting proteins with cardiac arrhythmias, and parallel analyses have suggested roles for these mutations in dysregulating Nav1.5 channel functional expression. However, the mechanisms whereby such native alterations in Nav1.5 function are achieved require identification and functional analysis of in situ Nav1.5 channels. The goal of the present proposal, therefore, is (1) to characterize the native components of Nav1.5 channel complexes, as well as PTM of these components, in the heart, by the use of mass spectrometry analyses; (2) to investigate the role(s) of the previously identified accessory subunit ankyrin G in regulating the functional expression of Nav1.5-encoded INa channels; and (3) to analyze the regulation defects associated with the E1053K mutation in Nav1.5 associated with Brugada syndrome, at the molecular, cellular and whole-animal levels. Altogether, the research proposed will improve our scientific knowledge about ion channel regulation in normal and diseased cardiac excitability, which is needed for improved identification, prevention and treatment of cardiac arrhythmias.
Champ scientifique
- medical and health sciencesclinical medicinecardiologycardiovascular diseasescardiac arrhythmia
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesmathematicspure mathematicsmathematical analysisfunctional analysis
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Appel à propositions
FP7-PEOPLE-2009-RG
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Régime de financement
MC-IRG - International Re-integration Grants (IRG)Coordinateur
44035 NANTES CEDEX 1
France