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Regulation of Na+ channel inactivation by the DIII and DIV voltage-sensing domains.


ABSTRACT: Functional eukaryotic voltage-gated Na+ (NaV) 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 NaV 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 NaV 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.

SUBMITTER: Hsu EJ 

PROVIDER: S-EPMC5339511 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Regulation of Na<sup>+</sup> channel inactivation by the DIII and DIV voltage-sensing domains.

Hsu Eric J EJ   Zhu Wandi W   Schubert Angela R AR   Voelker Taylor T   Varga Zoltan Z   Silva Jonathan R JR  

The Journal of general physiology 20170223 3


Functional eukaryotic voltage-gated Na<sup>+</sup> (Na<sub>V</sub>) 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<sub>V</sub> 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 fluorome  ...[more]

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