Regulation of Na Channel Inactivation by the DIII and DIV Voltage-sensing Domains

Overview

Journal J Gen Physiol

Specialty Physiology

Date 2017 Feb 25

PMID 28232510

Citations 24

Authors

Eric J Hsu

Wandi Zhu

Angela R Schubert

Taylor Voelker

Zoltan Varga

Jonathan R Silva

Affiliations

Soon will be listed here.

Abstract

Functional eukaryotic voltage-gated Na (Na) channels comprise four domains (DI-DIV), each containing six membrane-spanning segments (S1-S6). Voltage sensing is accomplished by the first four membrane-spanning segments (S1-S4), which together form a voltage-sensing domain (VSD). A critical Na channel gating process, inactivation, has previously been linked to activation of the VSDs in DIII and DIV. Here, we probe this interaction by using voltage-clamp fluorometry to observe VSD kinetics in the presence of mutations at locations that have been shown to impair Na channel inactivation. These locations include the DIII-DIV linker, the DIII S4-S5 linker, and the DIV S4-S5 linker. Our results show that, within the 10-ms timeframe of fast inactivation, the DIV-VSD is the primary regulator of inactivation. However, after longer 100-ms pulses, the DIII-DIV linker slows DIII-VSD deactivation, and the rate of DIII deactivation correlates strongly with the rate of recovery from inactivation. Our results imply that, over the course of an action potential, DIV-VSDs regulate the onset of fast inactivation while DIII-VSDs determine its recovery.

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