Voltage-gated ion channels are ubiquitously expressed in human tissues where they play diverse physiological functions such as the generation and modulation of the electrical activity in excitable tissues, myocyte contraction, modulation of neurotransmitter and hormone release. Mutations and/or altered regulation of these channels are associated to many pathologies such as neuronal, cardiac and muscular diseases. As a result, structural and functional characterization of those channels will certainly lead to new pharmacological, genetic and cellular therapies.
Crystallization of voltage-gated potassium (Kv) and sodium (Nav) channels provided a lot of information on their structure, and represented a new template for investigations on their molecular characteristics. This allowed us to shed light on the molecular mechanism of a cardiac Kv and a skeletal muscle Nav channel voltage-dependency. We showed that the channel protein contains an intramolecular ligand (the linker between the fourth and the fifth transmembrane domain, S4-S5) that binds to the channel gate (S6) and locks it in a closed state, in a voltage-dependent fashion. This channel property allowed us constructing inhibitory S4-S5 peptides and activatory S6 peptides.
We now want to test if the channels regulation by S4-S5 and S6 peptides may be of therapeutical interest, first in the context of cardiac and skeletal muscle pathologies. First we will study the structural details of the S4-S5/S6 interaction to improve the peptides efficacy. This will be done with the help of different molecular and structural tools that are available in the laboratory of Dan Minor: Nuclear Magnetic Resonance, isothermal titration calorimetry, circular dichroism…Second we will develop in vivo tests to validate the peptides therapeutical interest.
More generally, this project will help me in reinforcing the competitiveness of the group in “biophysics to bedside” studies.
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