Relative Voltage Sensor Activation Kinetics Determines the Effects of Sensor Neutralization in Voltage-Gated Sodium Channels

Abstract

Voltage-gated sodium (Nav) channels play a critical role in regulating the dynamics of electrophysiological systems. The gating kinetics of these channels are determined by the asynchronous movements of four voltage-sensing domains (VSDs). Over the last 40 years, a gating model has emerged whereby the movement of domains I to III are sufficient for pore opening whereas domain IV movement is sufficient and rate-limiting for channel inactivation. Our observations following charge neutralization of each VSD appear to differ from this viewpoint. Although domain IV movement is alone sufficient for channel inactivation, we found that neutralizing of any VSD facilitates inactivation in Nav1.5, in contrast to previous observations in Nav1.4. Through voltage-clamp fluorometry and mathematical modelling, we conclude that these disparate results are a consequence of differing domain activation sequences. Our analysis of a revised Nav channel gating model details how inter-domain coupling can interact with the relative movement kinetics of each domain to give rise to various consequences of altered VSD movement. Our modelling results thus reconcile contrasting experimental observations and predict a novel form of gating modulation.