Lipid Reguation of Voltage-gated Sodium Channels
电压门控钠通道的脂质调节
基本信息
- 批准号:435649-2013
- 负责人:
- 金额:$ 2.33万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2017
- 资助国家:加拿大
- 起止时间:2017-01-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
与所有离子通道一样,电压门控钠(Nav)通道是跨越脂质双层的蛋白质,允许离子从细胞膜的一侧传导到另一侧。因此,离子通道与它们嵌入其中的脂类密切相互作用。近年来,我们越来越认识到细胞内脂类结构的复杂性和动态性,它们在空间和时间上都是不同的,细胞膜的物理化学性质(头部基团、酰基尾部不饱和度、疏水厚度、曲率)可能通过直接和间接的脂蛋白相互作用来调节蛋白质的功能。然而,尽管离子通道与膜的密切相互作用可能是其功能的主要决定因素,但离子通道的脂质调节在很大程度上仍未确定。这是因为直到最近,由于无法获得纯化的离子通道,以及这些研究只能在脂质成分复杂、知之甚少和难以控制的细胞中进行,因此解决离子通道的脂质调节问题的努力在很大程度上仍然是定性的。鉴于我之前对其他离子通道的研究,我假设NAV通道是由嵌入它们的膜脂的物理化学性质调节的。最近,在纯化NAV通道的功能细菌同源物方面取得了关键突破,使我们能够通过将纯化的细菌NAV蛋白重组成特定组成的脂质体来检查它们的脂质依赖性。将这一方法与其他生物物理和结构技术(脂质结合分析、通量分析、电生理记录、LRET、SAXS和质谱仪)相结合,将使我们能够将对脂质调节的理解扩展到一类新的通道,揭示NAV通道中新的调节机制,并了解其调节的分子基础。这些数据将使我们能够揭示NAV通道中的新调节机制,这些机制在细胞系统中是无法获得的,并为电压门控离子通道中脂类调节的收敛或发散进化提供洞察力。
项目成果
期刊论文数量(0)
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DAvanzo, Nazzareno其他文献
DAvanzo, Nazzareno的其他文献
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Regulation of HCN channels by lipids and auxiliary subunits
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Regulation of HCN channels by lipids and auxiliary subunits
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$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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