Voltage-gated ion channel modulation by lipids: Insights from molecular dynamics simulations
Voltage-gated ion channel modulation by lipids: Insights from molecular dynamics simulations
复制标题
DOI：
10.1016/j.bbamem.2014.01.024
复制
发表时间：
2014-05-01
影响因子：
3.4
通讯作者：
Delemotte, Lucie
中科院分区：
文献类型：
--
作者：
Kasimova, Marina A.;Tarek, Mounir;Delemotte, Lucie
细胞通常使用脂质来调节离子通道的功能。脂质含量影响离子电流的振幅，改变电压门控离子通道处于活性或静息状态的概率。从各种技术和分子动力学研究中推断出的实验结果揭示了脂质头基团和离子通道残基之间的直接相互作用，表明对离子通道功能有影响。另一方面，脂质的改变原则上可能改变通道的整体静电环境，从而改变跨膜电位，导致间接调制，即全局效应。在这里，我们研究了嵌入双层中的电压门控钾通道Kv1.2的结构和动力学特性，这些通道的上部或下部小叶组成经过修改，对应于现实的生物学情景。第一个与鞘磷脂酶的作用有关，鞘磷脂酶是一种改变外膜小叶脂质组成的酶，第二个与一小部分PIP2存在的作用有关，PIP2是一种高度带负电荷的脂质，已知可调节电压门控通道功能。我们的分子动力学模拟不能排除前一种情况下的全局效应机制。然而，对于后者，表明离子通道和脂质头基团之间的局部相互作用是调制的关键因素。(C) 2014 Elsevier B.V.版权所有
Cells commonly use lipids to modulate the function of ion channels. The lipid content influences the amplitude of the ionic current and changes the probability of voltage-gated ion channels being in the active or in the resting states. Experimental findings inferred from a variety of techniques and molecular dynamics studies have revealed a direct interaction between the lipid headgroups and the ion channel residues, suggesting an influence on the ion channel function. On the other hand the alteration of the lipids may in principle modify the overall electrostatic environment of the channel, and hence the transmembrane potential, leading to an indirect modulation, i.e. a global effect Here we have investigated the structural and dynamical properties of the voltage-gated potassium channel Kv1.2 embedded in bilayers with modified upper or lower leaflet compositions corresponding to realistic biological scenarios: the first relates to the effects of sphingomyelinase, an enzyme that modifies the composition of lipids of the outer membrane leaflets, and the second to the effect of the presence of a small fraction of PIP2, a highly negatively charged lipid known to modulate voltage-gated channel function. Our molecular dynamics simulations do not enable to exclude the global effect mechanism in the former case. For the latter, however, it is shown that local interactions between the ion channel and the lipid headgroups are key-elements of the modulation. (C) 2014 Elsevier B.V. All rights reserved.