Obiettivo
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.
Campo scientifico
- medical and health sciencesbasic medicinemedicinal chemistry
- natural scienceschemical sciencesinorganic chemistryalkali metals
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesbasic medicinepharmacology and pharmacy
Invito a presentare proposte
FP7-PEOPLE-2009-RG
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Meccanismo di finanziamento
MC-IRG - International Re-integration Grants (IRG)Coordinatore
3000 Leuven
Belgio