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

Hsu, Eric J and Zhu, Wandi and Schubert, Angela R and Voelker, Taylor and Varga, Zoltan and Silva, Jonathan R (2017) Regulation of Na(+) channel inactivation by the DIII and DIV voltage-sensing domains. The Journal of general physiology, 149 (3). pp. 389-403. ISSN 1540-7748

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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.

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