ArticleThe Journal of physiology2007
Charge at the lidocaine binding site residue Phe-1759 affects permeation in human cardiac voltage-gated sodium channels.
Article in The Journal of physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 78 citations in OpenAlex.
- Late IMedicinal research reviews · 2026Review
- The local anesthetic, lidocaine, suppresses the growth of colon cancer SW480 cells by decreasing the voltage-gated sodium channel subunit NaScientific reports · 2025Article
- A governance of ion selectivity based on the occupancy of the "beacon" in one- and four-domain calcium and sodium channels.Channels (Austin, Tex.) · 2023Article
- Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.JCI insight · 2021Article
- Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin.Circulation · 2021Article
- Heterogeneity of the action potential duration is required for sustained atrial fibrillation.JCI insight · 2019Article
- 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
- Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants.The Journal of general physiology · 2017Article
- Role of protein kinase C in metabolic regulation of the cardiac NaHeart rhythm · 2017Article
- Modeling the human NaDrug design, development and therapy · 2017Article
- Pain transduction: a pharmacologic perspective.Expert review of clinical pharmacology · 2016Review
- Reconstitution of Human Ion Channels into Solvent-free Lipid Bilayers Enhanced by Centrifugal Forces.Biophysical journal · 2016Article
- Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice.The Journal of clinical investigation · 2016Article
- Understanding Sodium Channel Function and Modulation Using Atomistic Simulations of Bacterial Channel Structures.Current topics in membranes · 2016Article
- Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins.Channels (Austin, Tex.) · 2016Article
- The hitchhiker's guide to the voltage-gated sodium channel galaxy.The Journal of general physiology · 2016Review
- Properties of protein drug target classes.PloS one · 2015Article
- Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- The mechanism of Na⁺/K⁺ selectivity in mammalian voltage-gated sodium channels based on molecular dynamics simulation.Biophysical journal · 2013Article
- Analysis of the selectivity filter of the voltage-gated sodium channel Na(v)Rh.Cell research · 2013Article
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6 authors at 2 institutions in 1 country.
Funding
Abstract
Our homology molecular model of the open/inactivated state of the Na(+) channel pore predicts, based on extensive mutagenesis data, that the local anaesthetic lidocaine docks eccentrically below the selectivity filter, such that physical occlusion is incomplete. Electrostatic field calculations suggest that the drug's positively charged amine produces an electrostatic barrier to permeation. To test the effect of charge at this pore level on permeation in hNa(V)1.5 we replaced Phe-1759 of domain IVS6, the putative binding site for lidocaine's alkylamino end, with positively and negatively charged residues as well as the neutral cysteine and alanine. These mutations eliminated use-dependent lidocaine block with no effect on tonic/rested state block. Mutant whole cell currents were kinetically similar to wild type (WT). Single channel conductance (gamma) was reduced from WT in both F1759K (by 38%) and F1759R (by 18%). The negatively charged mutant F1759E increased gamma by 14%, as expected if the charge effect were electrostatic, although F1759D was like WT. None of the charged mutations affected Na(+)/K(+) selectivity. Calculation of difference electrostatic fields in the pore model predicted that lidocaine produced the largest positive electrostatic barrier, followed by lysine and arginine, respectively. Negatively charged glutamate and aspartate both lowered the barrier, with glutamate being more effective. Experimental data were in rank order agreement with the predicted changes in the energy profile. These results demonstrate that permeation rate is sensitive to the inner pore electrostatic field, and they are consistent with creation of an electrostatic barrier to ion permeation by lidocaine's charge.
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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.