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Deconstructing the function and pharmacology of voltage-activated sodium channels: novel perspectives for drug design

Objective

Previously, we used voltage-activated potassium (Kv) channels as reporters to identify and examine the contributions of individual voltage-activated sodium (Nav) channel paddle motifs to the kinetics of voltage sensor activation and to toxin receptors (Bosmans et al., 2008). Inspired by our results, we now want to deconstruct the function and pharmacology of Nav1.9, a channel of which our knowledge is very rudimentary because no pharmacological agents are available. Furthermore, attempts to express this channel in a heterologous expression system have failed. Our chimaera approach can reveal if Nav1.9 contains paddle motifs that sense changes in membrane voltage which, in turn, can activate the channel. Functional chimaeras of Nav1.9 with Kv channels will be used to screen for agents that interact with this channel. Extrapolation of the obtained results will enable us to identify and study Nav1.9 in its native environment. We are also interested in exploring the relationship between Nav channel paddle motifs with the surrounding lipid environment. Based on our previous results, we hypothesize that interactions of one specific paddle with lipids are unique and are responsible for slowing voltage sensor activation. We want to investigate this hypothesis by studying the effects of membrane lipid modifications on Nav channel chimaeras, on wild-type Nav channel kinetics and on toxin interaction. Finally, we are interested in learning more about the working mechanism and pharmacology of Nav channels in relation to their auxiliary beta-subunits. These subunits modulate Nav channel activity and are involved in several pathophysiological disorders. We are particularly interested in determining whether beta-subunits can modulate the pharmacology of Nav channels. If so, we will try to unravel the underlying mechanisms.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/lipids
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /medical and health sciences/basic medicine/pharmacology and pharmacy

Call for proposal

FP7-PEOPLE-2009-RG
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Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
Address
Oude Markt 13
3000 Leuven
Belgium
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 75 000
Administrative Contact
Stijn Delauré (Dr.)