Lipid Reguation of Voltage-gated Sodium Channels

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Voltage-gated sodium (Nav) channels, like all ion channels, are proteins that span across the lipid bilayer to allow for the conduction of ions from one side of a cellular membrane to the other. Thus, ion channels intimately interact with the lipids in which they are embedded. In recent years, we are now gaining appreciation for the complexity and dynamic nature of the lipid landscape, which vary both spatially and temporally within a cell, and that the physiochemical properties of the cell membrane (headgroup, degree of acyl tail unsaturation, hydrophobic thickness, curvature) may regulate the function of proteins through direct and indirect lipid-protein interactions. However, although the intimate interaction of ion channels with the membrane can be a major determinant of their function, lipid regulation of ion channels remains largely uncharacterized. This is because until recently, efforts to address lipid regulation of ion channels remained largely qualitative because of the inability to obtain purified channels and because these studies could be only performed in cells where lipid composition is complex, poorly understood and difficult to control. In view of my previous work with other ion channels, I hypothesize that Nav channels are regulated by the physiochemical properties of the membrane lipids in which they are embedded. Critical breakthroughs in purifying functional bacterial homologues of Nav channels have been recently made, enabling us to examine their lipid dependence by reconstituting purified bacterial Nav proteins into liposomes of defined composition. Combining this approach with other biophysical and structural techniques (lipid binding assays, flux assays, electrophysiological recordings, LRET, SAXS, and mass spectrometry) will enable us to expand our understanding of lipid regulation to a new class of channels, to uncover novel mechanisms of regulation in Nav channels and understand the underlying molecular basis for their lipid regulation. These data will allow us to uncover novel mechanisms of regulation in Nav channels that are otherwise unobtainable in cellular systems and provide insights into the convergent or divergent evolution of lipid regulation in voltage-gated ion channels.