Mechanism of Voltage Gating in Potassium Channels

作者：Morten Ø. Jensen, Vishwanath Jogini, David W. Borhani, Abba E. Leffler, Ron O. Dror, David Elliot Shaw · 发表于：Science · 年份：2012 · DOI：10.1126/science.1216533 · 被引用次数：629 · 研究领域：Ion channel regulation and function、Lipid Membrane Structure and Behavior、Neuroscience and Neural Engineering

The mechanism of ion channel voltage gating-how channels open and close in response to voltage changes-has been debated since Hodgkin and Huxley's seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD-pore linker, perturbing linker-S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. We propose a mechanistic model for the sodium/potassium/calcium voltage-gated ion channel superfamily that reconciles apparently conflicting experimental data.