ArticleCirculation research2009
Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.
Article in Circulation research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
37 citing papers in PubMed, 68 citations in OpenAlex.
- Predicting Patient Response to the Antiarrhythmic Mexiletine Based on Genetic Variation.Circulation research · 2019Trial
- Suzetrigine: a novel allosteric voltage-gated sodium 1.8 channel inhibitor, thereby stabilizing the closed state of the channel.The Korean journal of pain · 2026Article
- Modulation of Voltage-Gated Sodium Channels from Sensory Neurons by Isoeugenol.International journal of molecular sciences · 2025Article
- Molecular Pharmacology of Selective NaACS chemical neuroscience · 2024Article
- Article
- 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
- Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog.Scientific reports · 2018Article
- Multiple targets for flecainide action: implications for cardiac arrhythmogenesis.British journal of pharmacology · 2018Review
- State-dependent block of voltage-gated sodium channels by the casein-kinase 1 inhibitor IC261.Investigational new drugs · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Modeling the human NaDrug design, development and therapy · 2017Article
- Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins.Channels (Austin, Tex.) · 2016Article
- Important Role of Asparagines in Coupling the Pore and Votage-Sensor Domain in Voltage-Gated Sodium Channels.Biophysical journal · 2015Article
- Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling.Scientific reports · 2015Article
- Harry A. Fozzard, MD: 1931–2014.Circulation research · 2015Article
- Comparison of Gating Properties and Use-Dependent Block of Nav1.5 and Nav1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine.PloS one · 2015Article
- Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism.The Journal of general physiology · 2014Article
- Ranolazine inhibition of hERG potassium channels: drug-pore interactions and reduced potency against inactivation mutants.Journal of molecular and cellular cardiology · 2014Article
- Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.Neuroscience bulletin · 2014Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
rationaleLidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in Na(V)1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block.
objectiveMeasurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes. METHODS AND
resultsThe measurements showed that replacement of Phe1759 with a nonaromatic residue permits clear separation of action of lidocaine and benzocaine into 2 components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4s in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed.
conclusionsThese 2 components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the 2 binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs.
Indexed as
Identifiers
What OpenQuestion holds
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.