The voltage-gated ion channel activity depends on both activation (transition from the resting state to the open state) and inactivation. Inactivation is a self-restraint mechanism to limit ion conduction and is as crucial to membrane excitability as activation. Inactivation can occur when the channel is open or closed. Although open-state inactivation is well understood, the molecular basis of closed-state inactivation has remained elusive. We report cryo-EM structures of human K_V4.2 channel complexes in inactivated, open, and closed states. Closed-state inactivation of K_V4 involves an unprecedented symmetry breakdown for pore closure by only two of the four S4–S5 linkers, distinct from known mechanisms of open-state inactivation. We further capture K_V4 in a putative resting state, revealing how voltage sensor movements control the pore. Moreover, our structures provide insights regarding channel modulation by KChIP2 and DPP6 auxiliary subunits. Our findings elucidate mechanisms of closed-state inactivation and voltage-dependent activation of the K_V4 channel.

电压门控离子通道活性取决于激活（从静止状态到开放状态的转变）和失活。失活是一种限制离子传导的自我约束机制，与激活一样对膜兴奋性至关重要。当通道打开或关闭时，可能会发生失活。尽管开放态失活已被充分理解，但封闭态失活的分子基础仍然难以捉摸。_{我们报告了人类 K V} 4.2 通道复合物在失活、开放和关闭状态下的冷冻电镜结构。_{K V} 4的闭合状态失活涉及前所未有的对称性破坏，仅通过四个 S4-S5 连接体中的两个来关闭孔，这与已知的开放状态失活机制不同。我们进一步捕获K _V4 处于假定的静止状态，揭示了电压传感器运动如何控制毛孔。此外，我们的结构提供了有关 KChIP2 和 DPP6 辅助亚基通道调制的见解。_{我们的研究结果阐明了 K V} 4 通道的闭合状态失活和电压依赖性激活的机制。