美国国立卫生研究院Kenton J. Swartz团队近日取得一项新成果。经过不懈努力，他们研究出K_v通道快速N型失活的结构基础。2025年8月6日出版的《自然》杂志发表了这项成果。

本研究利用低温电子显微镜、质谱分析和电生理学方法研究了振动器K_v通道快速失活的机制。该课题组研究人员解决了完全失活状态的结构，其中N端非极性端以扩展构象插入内部孔。N端蛋氨酸被删除，留下乙酰化的丙氨酸，并与孔壁异亮氨酸残基相互作用，其中RNA编辑调节快速失活。内部激活门的打开是快速失活所必需的，因为它使塞结构域能够阻塞孔并重新定位门残基以与该结构域相互作用并稳定该结构域。研究人员还表明，外部K⁺通过改变离子选择性过滤器的构象而不是通过静电斥力使失活状态不稳定。这些发现建立了K_v通道快速失活的机制，揭示了RNA编辑和N端乙酰化是如何调控K_v通道的，并为理解其他电压激活通道的相关机制提供了框架。

据介绍，动作电位是通过打开电压激活的钠（Na_v）和钾（K_v）通道产生的，它们可以迅速失活以形成神经冲动，并有助于突触促进和短期记忆。快速失活的机制涉及细胞内结构域，该结构域阻断了Na_v和K_v通道的内部孔；然而，最近对Na_v和K_v通道的研究支持在失活期间内部孔隙关闭的机制。

附：英文原文

Title: Structural basis of fast N-type inactivation in Kv channels

Author: Tan, Xiao-Feng, Fernndez-Mario, Ana I., Li, Yan, Chang, Tsg-Hui, Swartz, Kenton J.

Issue&Volume: 2025-08-06

Abstract: Action potentials are generated by opening of voltage-activated sodium (Nav) and potassium (Kv) channels1, which can rapidly inactivate to shape the nerve impulse and contribute to synaptic facilitation and short-term memory1,2,3,4. The mechanism of fast inactivation was proposed to involve an intracellular domain that blocks the internal pore in both Nav5,6 and Kv7,8,9 channels; however, recent studies in Nav10,11 and Kv12,13 channels support a mechanism in which the internal pore closes during inactivation. Here we investigate the mechanism of fast inactivation in the Shaker Kv channel using cryo-electron microscopy, mass spectrometry and electrophysiology. We resolved structures of a fully inactivated state in which the non-polar end of the N terminus plugs the internal pore in an extended conformation. The N-terminal methionine is deleted, leaving an alanine that is acetylated and interacts with a pore-lining isoleucine residue where RNA editing regulates fast inactivation14. Opening of the internal activation gate is required for fast inactivation because it enables the plug domain to block the pore and repositions gate residues to interact with and stabilize that domain. We also show that external K+ destabilizes the inactivated state by altering the conformation of the ion selectivity filter rather than by electrostatic repulsion. These findings establish the mechanism of fast inactivation in Kv channels, revealing how it is regulated by RNA editing and N-terminal acetylation, and providing a framework for understanding related mechanisms in other voltage-activated channels.

DOI: 10.1038/s41586-025-09339-7

Source: https://www.nature.com/articles/s41586-025-09339-7