ArticleThe Journal of physiology2004
Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block.
Article in The Journal of physiology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 28 papers, 1 of them a synthesis that pooled it.
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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
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- A clinical prediction rule for myotonia permanens associated with theCurrent research in neurobiology · 2026Article
- High-throughput screens identify genotype-specific therapeutics for channelopathies.JCI insight · 2025Article
- Article
- Effects of NaCell biochemistry and biophysics · 2025Review
- Pharmacological therapy of non-dystrophic myotonias.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2025Review
- Functional effects of drugs and toxins interacting with NaFrontiers in pharmacology · 2024Review
- Blockers of Skeletal Muscle NaInternational journal of molecular sciences · 2023Review
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2022Review
- Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity.The Journal of general physiology · 2021Article
- Long-Term Safety and Usefulness of Mexiletine in a Large Cohort of Patients Affected by Non-dystrophic Myotonias.Frontiers in neurology · 2020Article
- SCN4A as modifier gene in patients with myotonic dystrophy type 2.Scientific reports · 2018Article
- A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels.Scientific reports · 2018Article
- Flecainide-Induced Brugada Syndrome in a Patient With Skeletal Muscle Sodium Channelopathy: A Case Report With Critical Therapeutical Implications and Review of the Literature.Frontiers in neurology · 2018Article
- Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2017Article
- Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.Neuropharmacology · 2017Article
- Translational approach to address therapy in myotonia permanens due to a new SCN4A mutation.Neurology · 2016Article
- Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery.Frontiers in pharmacology · 2016Review
- Preclinical evaluation of marketed sodium channel blockers in a rat model of myotonia discloses promising antimyotonic drugs.Experimental neurology · 2014Article
Corrections and comments
- Erratum issuedLuca, Annamaria D E [corrected to De Luca, Annamaria]
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Flecainide, a class IC antiarrhythmic, was shown to improve myotonia caused by sodium channel mutations in situations where the class IB antiarrhythmic drug mexiletine was less efficient. Yet little is known about molecular interactions between flecainide and human skeletal muscle sodium (hNa(v)1.4) channels. Whole-cell sodium currents (I(Na)) were recorded in tsA201 cells expressing wild-type (WT) and mutant hNa(v)1.4 channels (R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia). At a holding potential (HP) of -120 mV, flecainide use-dependently blocked WT and G1306E I(Na) equally but was more potent on R1448C channels. For WT, the extent of block depended on a holding voltage more negative than the activation threshold, being greater at -90 mV as compared to -120 and -180 mV. This behaviour was exacerbated by the R1448C mutation since block at -120 mV was greater than that at -180 mV. Thus flecainide can bind to inactivated sodium channels in the absence of channel opening. Nevertheless, all the channels showed the same closed-state affinity constant (K(R) approximately 480 microM) and the same inactivated-state affinity constant (K(I) approximately 18 microM). Simulations according to the modulated receptor hypothesis mimic the voltage-dependent block of WT and mutant channels by flecainide and mexiletine. All the results suggest similar blocking mechanisms for the two drugs. Yet, since flecainide exerts use-dependent block at lower frequency than mexiletine, it may exhibit greater benefit in all myotonic syndromes. Moreover, flecainide blocks hNa(v)1.4 channel mutants with a rightward shift of availability voltage dependence more specifically than mexiletine, owing to a lower K(R)/K(I) ratio. This study offers a pharmacogenetic strategy to better address treatment in individual myotonic patients.
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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.