ArticlePloS one2017
Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.Circulation research · 2019Trial
- When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of NaCells · 2022Review
- The L1624Q Variant inFrontiers in pharmacology · 2021Article
- E1784K, the most common Brugada syndrome and long-QT syndrome type 3 mutant, disrupts sodium channel inactivation through two separate mechanisms.The Journal of general physiology · 2020Article
- An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF.The Journal of general physiology · 2020Article
- Pilsicainide Administration Unmasks a Phenotype of Brugada Syndrome in a Patient with Overlap Syndrome due to the E1784K SCN5A Mutation.Internal medicine (Tokyo, Japan) · 2020Article
- A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels.Scientific reports · 2018Article
- The efficacy of Ranolazine on E1784K is altered by temperature and calcium.Scientific reports · 2018Article
- Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3.Channels (Austin, Tex.) · 2018Article
- Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.Channels (Austin, Tex.) · 2018Article
- Arrhythmogenic triggers associated with Sudden Cardiac Death.Channels (Austin, Tex.) · 2018Review
Corrections and comments
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Authors and funding
5 authors.
Funding
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.
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