ArticleThe Journal of general physiology2010
Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics.
Article in The Journal of general physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 51 citations in OpenAlex.
- Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.Circulation research · 2019Trial
- Nanoscale organization in the cell membrane dynamically modulates the biophysics of voltage-gated sodium channels.Nature communications · 2026Article
- Efficacy and safety of ketamine wound infiltration for postoperative pain management: a systematic review, meta-analysis, and trial sequential analysis.Annals of medicine and surgery (2012) · 2024Review
- Molecular Modeling of Cardiac Sodium Channel with Mexiletine.Membranes · 2022Article
- Efficacy and safety of wound infiltration modalities for postoperative pain management after cesarean section: a systematic review and network meta-analysis protocol.Systematic reviews · 2022Article
- Functional correlates of clinical phenotype and severity in recurrent SCN2A variants.Communications biology · 2022Article
- Sodium Channels and Local Anesthetics-Old Friends With New Perspectives.Frontiers in pharmacology · 2022Review
- Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.JCI insight · 2021Article
- The functionally relevant site for paxilline inhibition of BK channels.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- A Molecularly Detailed NaJACC. Basic to translational science · 2019Article
- QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons.Neurogastroenterology and motility · 2019Article
- Propofol inhibits prokaryotic voltage-gated NaThe Journal of general physiology · 2018Article
- Mechanisms of noncovalent β subunit regulation of NaThe Journal of general physiology · 2017Article
- Structures of closed and open states of a voltage-gated sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Regulation of NaThe Journal of general physiology · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons.Journal of neurophysiology · 2016Article
- The hitchhiker's guide to the voltage-gated sodium channel galaxy.The Journal of general physiology · 2016Review
- Important Role of Asparagines in Coupling the Pore and Votage-Sensor Domain in Voltage-Gated Sodium Channels.Biophysical journal · 2015Article
- Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations.Circulation. Arrhythmia and electrophysiology · 2015Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
The hallmark of many intracellular pore blockers such as tetra-alkylammonium compounds and local anesthetics is their ability to allosterically modify the movement of the voltage sensors in voltage-dependent ion channels. For instance, the voltage sensor of domain III is specifically stabilized in the activated state when sodium currents are blocked by local anesthetics. The molecular mechanism underlying this long-range interaction between the blocker-binding site in the pore and voltage sensors remains poorly understood. Here, using scanning mutagenesis in combination with voltage clamp fluorimetry, we systematically evaluate the role of the internal gating interface of domain III of the sodium channel. We find that several mutations in the S4-S5 linker and S5 and S6 helices dramatically reduce the stabilizing effect of lidocaine on the activation of domain III voltage sensor without significantly altering use-dependent block at saturating drug concentrations. In the wild-type skeletal muscle sodium channel, local anesthetic block is accompanied by a 21% reduction in the total gating charge. In contrast, point mutations in this critical intracellular region reduce this charge modification by local anesthetics. Our analysis of a simple model suggests that these mutations in the gating interface are likely to disrupt the various coupling interactions between the voltage sensor and the pore of the sodium channel. These findings provide a molecular framework for understanding the mechanisms underlying allosteric interactions between a drug-binding site and voltage sensors.
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Registered trials
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.