ArticleThe Journal of general physiology2013
Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels.
Article in The Journal of general physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.
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Who cites it
131 citing papers in PubMed, 229 citations in OpenAlex.
- Electrophysiological characteristics of a SCN5A voltage sensors mutation R1629Q associated with Brugada syndrome.PloS one · 2013Trial
- Voltage-sensing domains: structural and functional diversity.European biophysics journal : EBJ · 2026Review
- Calmodulin acts as a selective switch in FGF12A-mediated regulation of the cardiac sodium channel Nav1.5.The Journal of biological chemistry · 2026Article
- Electrostatic tuning of NaThe Journal of physiology · 2026Article
- Long-term inactivation mediated by different FGF-A homologues on heterologously expressed NaV1.2 currents.The Journal of general physiology · 2026Article
- Multiscale computational analysis reveals enhanced allosteric modulation of Nav1.5 by dual binding of dapagliflozin and ertugliflozin.Scientific reports · 2025Article
- Molecular basis of sodium channel inactivation.Nature communications · 2025Article
- Recent advances in the pharmacology of voltage-gated ion channels.Pharmacological reviews · 2025Review
- Article
- Charge Reversal of the Uppermost Arginine in Sliding Helix S4-I Affects Gating of Cardiac Sodium Channel.International journal of molecular sciences · 2025Article
- A sodium channel mutant removes fast inactivation with the inactivation particle bound.The Journal of general physiology · 2025Article
- Differential Inhibition by Cenobamate of Canonical Human Nav1.5 Ion Channels and Several Point Mutants.International journal of molecular sciences · 2025Article
- Harnessing Deep Learning Methods for Voltage-Gated Ion Channel Drug Discovery.Physiology (Bethesda, Md.) · 2025Review
- Inhibitory Effects of Cenobamate on Multiple Human Cardiac Ion Channels and Possible Arrhythmogenic Consequences.Biomolecules · 2024Article
- An all-atom model of the human cardiac sodium channel in a lipid bilayer.Scientific reports · 2024Article
- Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.iScience · 2024Article
- An artificial intelligence accelerated virtual screening platform for drug discovery.Nature communications · 2024Article
- Resurgent current in context: Insights from the structure and function of Na and K channels.Biophysical journal · 2024Review
- Conformational photo-trapping in NaBiophysical journal · 2024Article
- Article
71 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Voltage-gated sodium channels are critical for the generation and propagation of electrical signals in most excitable cells. Activation of Na(+) channels initiates an action potential, and fast inactivation facilitates repolarization of the membrane by the outward K(+) current. Fast inactivation is also the main determinant of the refractory period between successive electrical impulses. Although the voltage sensor of domain IV (DIV) has been implicated in fast inactivation, it remains unclear whether the activation of DIV alone is sufficient for fast inactivation to occur. Here, we functionally neutralize each specific voltage sensor by mutating several critical arginines in the S4 segment to glutamines. We assess the individual role of each voltage-sensing domain in the voltage dependence and kinetics of fast inactivation upon its specific inhibition. We show that movement of the DIV voltage sensor is the rate-limiting step for both development and recovery from fast inactivation. Our data suggest that activation of the DIV voltage sensor alone is sufficient for fast inactivation to occur, and that activation of DIV before channel opening is the molecular mechanism for closed-state inactivation. We propose a kinetic model of sodium channel gating that can account for our major findings over a wide voltage range by postulating that DIV movement is both necessary and sufficient for fast inactivation.
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