# Molecular Basis of Sodium Channel Inactivation

## TL;DR

This paper explains how sodium channels inactivate quickly using a new 'lock and key' model based on structural and functional experiments.

## Contribution

The study proposes a novel 'lock and key' model for sodium channel inactivation, replacing the outdated 'ball and chain' model.

## Key findings

- Fast inactivation occurs in less than 2 milliseconds through a structural rearrangement involving the IFM motif and pore-forming helices.
- The IFM motif interacts with S6 segments of DIV and DIIII via hydrophobic and aromatic interactions after voltage-sensor activation.
- The proposed 'lock and key' model explains how the hydrophobic gate in the pore is exposed and closed during inactivation.

## Abstract

Voltage-gated sodium channels initiate action potentials and control electrical signaling throughout the animal kingdom. Fast inactivation is an essential auto-inhibitory mechanism and requisite component of sodium channel physiology. Recent structural and electrophysiological results are inconsistent with the canonical “ball and chain” model of fast inactivation thus necessitating an updated theoretical framework. Here, we use encoded fluorescence spectroscopy and high-resolution electrophysiology to capture key steps in the fast inactivation mechanism, from voltage-sensor activation to pore occlusion, an ultra-fast process which occurs in less than 2 milliseconds. Upon depolarization, activation of the domain IV voltage sensor initiates cytoplasmic DIII_DIV linker movement and quickly repositions the IFM motif into a hydrophobic pocket adjacent to the pore. This triggers a structural rearrangement of the pocket. The phenylalanine of the IFM motif contacts the pore-forming helices via a hydrophobic interaction with S6 of DIV and an aromatic/hydrophobic interaction with S6 of DIIII. These two interactions occur only after both S6 segments rotate, thus exposing the hydrophobic gate into the pore producing the fast inactivation. Based on the current results, we propose an alternative “lock and key” model to explain the molecular mechanism of fast inactivation.