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Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation

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  • Colin H Peters
  • Alec Yu
  • Wandi Zhu
  • Jonathan R Silva
  • Peter C Ruben

Abstract

E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors. We measured ionic currents and gating currents at pH 7.4 and pH 6.0 in Xenopus laevis oocytes. Contrary to our expectation, the movement of gating charges is shifted to more hyperpolarized membrane potentials by E1784K. Voltage-clamp fluorimetry experiments show that this gating charge shift is due to the movement of the DIVS4 voltage-sensor being shifted to more hyperpolarized membrane potentials. Using a model and experiments on fast inactivation-deficient channels, we show that changes to the rate and voltage-dependence of fast inactivation are sufficient to shift the conductance curve in E1784K. Our results localize the effects of E1784K to DIVS4, and provide novel insight into the role of the DIV-VSD in regulating the voltage-dependencies of activation and fast inactivation.

Suggested Citation

  • Colin H Peters & Alec Yu & Wandi Zhu & Jonathan R Silva & Peter C Ruben, 2017. "Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation," PLOS ONE, Public Library of Science, vol. 12(9), pages 1-29, September.
    • Handle: RePEc:plo:pone00:0184605
    DOI: 10.1371/journal.pone.0184605
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    References listed on IDEAS

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    1. Qiuyun Chen & Glenn E. Kirsch & Danmei Zhang & Ramon Brugada & Josep Brugada & Pedro Brugada & Domenico Potenza & Angel Moya & Martin Borggrefe & Günter Breithardt & Rocio Ortiz-Lopez & Zhiqing Wang &, 1998. "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation," Nature, Nature, vol. 392(6673), pages 293-296, March.
    2. Zheng Zhang & Zhiwen Zhao & Yongfeng Liu & Wei Wang & Ying Wu & Jiuping Ding, 2013. "Kinetic Model of Nav1.5 Channel Provides a Subtle Insight into Slow Inactivation Associated Excitability in Cardiac Cells," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-8, May.
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