ArticleChannels (Austin, Tex.)2014
Investigating the size and dynamics of voltage-gated sodium channel fenestrations.
Article in Channels (Austin, Tex.), 2014. 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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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
23 citing papers in PubMed, 38 citations in OpenAlex.
- ARumenamides as Multitarget Ion Channel Modulators: Insights from Fenestration-Focused Docking, ADMET Profiling, and Molecular Dynamics.International journal of molecular sciences · 2026Article
- The Effects of 3-Methylphenanthrene on Ion Currents Mediated by KBulletin of experimental biology and medicine · 2025Article
- Drugs exhibit diverse binding modes and access routes in the Nav1.5 cardiac sodium channel pore.The Journal of general physiology · 2025Article
- The road to evolution of ProTx2: how to be a subtype-specific inhibition of human NaFrontiers in pharmacology · 2024Article
- Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors.Biophysical journal · 2022Article
- Article
- Fenestropathy of Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Review
- The Citrus Flavonoid Hesperetin Has an Inadequate Anti-Arrhythmic Profile in the ΔKPQ NaBiomolecules · 2020Article
- Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Noncanonical Ion Channel Behaviour in Pain.International journal of molecular sciences · 2019Review
- The effect of high pressure on the NMDA receptor: molecular dynamics simulations.Scientific reports · 2019Article
- Emerging Diversity in Lipid-Protein Interactions.Chemical reviews · 2019Review
- Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.Chemical reviews · 2019Review
- Role of the Interaction Motif in Maintaining the Open Gate of an Open Sodium Channel.Biophysical journal · 2018Article
- Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- New Cav2 calcium channel gating modifiers with agonist activity and therapeutic potential to treat neuromuscular disease.Neuropharmacology · 2018Article
- Isoflurane modulates activation and inactivation gating of the prokaryotic NaThe Journal of general physiology · 2017Article
- The discovery of a potent NaMedChemComm · 2017Article
- New potential binding determinant for hERG channel inhibitors.Scientific reports · 2016Article
- Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins.Channels (Austin, Tex.) · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Eukaryotic voltage-gated sodium channels (VGSCs) are essential for the initiation and propagation of action potentials in electrically excitable cells, and are important pharmaceutical targets for the treatment of neurological disorders such as epilepsy, cardiac arrhythmias, and chronic pain. Evidence suggests that small, hydrophobic, VGSC-blocking drugs can gain access to binding residues within the central cavity of these channels by passing through lateral, lipid-filled “fenestrations” which run between the exterior of the protein and its central pore. Here, we use molecular dynamics simulations to investigate how the size and shape of fenestrations change over time in several bacterial VGSC models and a homology model of Nav1.4. We show that over the course of the simulations, the size of the fenestrations is primarily influenced by rapid protein motions, such as amino acid side-chain rotation, and highlight that differences between fenestration bottleneck-contributing residues are the primary cause of variations in fenestration size between the 6 bacterial models. In the eukaryotic channel model, 2 fenestrations are wide, but 2 are narrow due to differences in the amino acid sequence in the 4 domains. Lipid molecules are found to influence the size of the fenestrations by protruding acylchains into the fenestrations and displacing amino acid side-chains. Together, the results suggest that fenestrations provide viable pathways for small, flexible, hydrophobic drugs.
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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.