ArticleNature communications2023
A mechanistic reinterpretation of fast inactivation in voltage-gated Na
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Evolution, hibernation, and inactivation of voltage-gated Na channels.The Journal of general physiology · 2026Review
- Long-term inactivation mediated by different FGF-A homologues on heterologously expressed NaV1.2 currents.The Journal of general physiology · 2026Article
- Mechanisms of SCN2A loss of function do not predict presence or phenotype of epilepsy.Epilepsia · 2026Article
- Structural and functional mechanisms underlying activation gate dynamics and IFM motif accessibility in human NaNature communications · 2026Article
- Molecular basis of sodium channel inactivation.Nature communications · 2025Article
- Closed state structure of the pore revealed by uncoupled Shaker KNature communications · 2025Article
- Structural basis of fast N-type inactivation in KNature · 2025Article
- Effects of open-channel blocking peptides in NaBiophysical journal · 2025Article
- Using metaphorical considerations to benefit research on the sodium channel fast inactivation mechanism.The Journal of general physiology · 2025Article
- The α/β3 complex of human voltage-gated sodium channel hNaJournal of molecular modeling · 2025Article
- Structural basis of human NaProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cardiac Electrophysiological Effects of the Sodium Channel-Blocking Antiepileptic Drugs Lamotrigine and Lacosamide.Pharmaceuticals (Basel, Switzerland) · 2025Article
- A sodium channel mutant removes fast inactivation with the inactivation particle bound.The Journal of general physiology · 2025Article
- Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization.Computational and structural biotechnology journal · 2025Article
- A unique mechanism of transfluthrin action revealed by mapping its binding sites in the mosquito sodium channel.Insect biochemistry and molecular biology · 2024Article
- Isoleucine gate blocks KeLife · 2024Article
- Conformational photo-trapping in NaBiophysical journal · 2024Article
- Resurgent current in context: Insights from the structure and function of Na and K channels.Biophysical journal · 2024Review
- Honeybee CaV4 has distinct permeation, inactivation, and pharmacology from homologous NaV channels.The Journal of general physiology · 2024Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
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Authors and funding
4 authors.
Funding
Abstract
The hinged-lid model was long accepted as the canonical model for fast inactivation in Nav channels. It predicts that the hydrophobic IFM motif acts intracellularly as the gating particle that binds and occludes the pore during fast inactivation. However, the observation in recent high-resolution structures that the bound IFM motif is located far from the pore, contradicts this preconception. Here, we provide a mechanistic reinterpretation of fast inactivation based on structural analysis and ionic/gating current measurements. We demonstrate that in Nav1.4 the final inactivation gate is comprised of two hydrophobic rings at the bottom of S6 helices. These rings function in series and close downstream of IFM binding. Reducing the volume of the sidechain in both rings leads to a partially conductive, leaky inactivated state and decreases the selectivity for Na
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.