小柯机器人

美国国立卫生研究院Kenton J. Swartz小组揭示通过机电耦合的Kv2.1通道失活。相关论文于2023年9月27日在线发表在《自然》杂志上。

研究人员利用冷冻电镜展示了Kv2.1通道在脂质环境中的结构，为探索其功能机制以及导致癫痫性脑病的突变如何改变通道活性提供了一个框架。通过对一系列致病突变的研究，研究人员发现其中一种突变揭示了孔隙内端附近的疏水耦合关系，该关系对失活至关重要。功能和结构研究都揭示出，Kv2.1的失活是由机电耦合的动态变化导致的，机电耦合的作用是重新定位内孔S6螺旋并关闭内孔。

将这些发现与其他Kv通道以及电压活化钠通道和钙通道的现有结构一起考虑，表明相关的失活机制在电压活化阳离子通道中是保守的，并且很可能被广泛使用的治疗药物所利用，从而实现通道活性的状态依赖性调节。

据悉，Kv2.1电压活化钾离子（Kv）通道是哺乳动物中枢神经系统中一个重要的延迟整流Kv通道，其激活和失活机制对调节神经元内在兴奋性至关重要。

附：英文原文

Title: Inactivation of the Kv2.1 channel through electromechanical coupling

Author: Fernndez-Mario, Ana I., Tan, Xiao-Feng, Bae, Chanhyung, Huffer, Kate, Jiang, Jiansen, Swartz, Kenton J.

Issue&Volume: 2023-09-27

Abstract: The Kv2.1 voltage-activated potassium (Kv) channel is a prominent delayed-rectifier Kv channel in the mammalian central nervous system, where its mechanisms of activation and inactivation are critical for regulating intrinsic neuronal excitability1,2. Here we present structures of the Kv2.1 channel in a lipid environment using cryo-electron microscopy to provide a framework for exploring its functional mechanisms and how mutations causing epileptic encephalopathies3,4,5,6,7 alter channel activity. By studying a series of disease-causing mutations, we identified one that illuminates a hydrophobic coupling nexus near the internal end of the pore that is critical for inactivation. Both functional and structural studies reveal that inactivation in Kv2.1 results from dynamic alterations in electromechanical coupling to reposition pore-lining S6 helices and close the internal pore. Consideration of these findings along with available structures for other Kv channels, as well as voltage-activated sodium and calcium channels, suggests that related mechanisms of inactivation are conserved in voltage-activated cation channels and likely to be engaged by widely used therapeutics to achieve state-dependent regulation of channel activity.

DOI: 10.1038/s41586-023-06582-8

Source: https://www.nature.com/articles/s41586-023-06582-8

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