Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of Micelle-forming amphiphiles and cholesterol.
Regulation of sodium channel function by bilayer elasticity: the importance of hydrophobic coupling. Effects of Micelle-forming amphiphiles and cholesterol.
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DOI：
10.1085/jgp.200308996
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发表时间：
2004-05
影响因子：
3.8
通讯作者：
Andersen, Olaf S
中科院分区：
文献类型：
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作者：
Lundbaek, Jens A;Birn, Pia;Hansen, Anker J;Sogaard, Rikke;Nielsen, Claus;Girshman, Jeffrey;Bruno, Michael J;Tape, Sonya E;Egebjerg, Jan;Greathouse, Denise V;Mattice, Gwendolyn L;Koeppe, Roger E 2nd;Andersen, Olaf S
膜蛋白受脂质双层组成的调节。很少涉及特定的脂质-蛋白质相互作用，这表明调节是由于一些一般双层性质（或性质）的变化。跨膜蛋白和周围双层之间的疏水偶联意味着蛋白质构象变化可能与可逆的局部双层变形有关。脂质双分子层是弹性体，并且双分子层变形的能量成本有助于蛋白质构象变化的总能量成本。因此，蛋白质构象变化的能量学和动力学将受到双层弹性的调节，这是由脂质组成决定的。这种疏水偶联机制已在短杆菌肽通道中被广泛研究，其中通道-双层疏水相互作用将“构象”变化（单体参与二聚体转变）链接到弹性双层变形。短杆菌肽通道因此受到脂质双层弹性性质（厚度、单层平衡曲率以及压缩和弯曲模量）的调节。为了研究这种疏水偶联机制是否可能是调节膜蛋白功能的一般机制，我们研究了HEK 293细胞中表达的电压依赖性平滑肌钠通道是否受双层弹性的调节，如使用短杆菌肽A（gA）通道所监测的。非生理性两亲物（β-辛基-葡糖苷、Genapol X-100、Triton X-100和还原Triton X-100）使脂质双层不那么“僵硬”，如使用gA通道测量的，使钠通道失活的电压依赖性向更超极化的电位偏移。在低两亲物浓度下，移位的幅度与gA通道寿命的变化线性相关。胆固醇耗竭，这也降低了双层刚度，导致类似的钠通道失活的转变。这些结果提供了强有力的支持的概念，双层蛋白疏水耦合允许的双层弹性特性，以调节膜蛋白的功能。
Membrane proteins are regulated by the lipid bilayer composition. Specific lipid–protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel–bilayer hydrophobic interactions link a “conformational” change (the monomer↔dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (β-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less “stiff”, as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer–protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function.