ArticleThe Journal of physiology2001
Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na(+) channel.
Article in The Journal of physiology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 43 citations in OpenAlex.
- Effectiveness and safety of mexiletine versus placebo in patients with myotonia: a systematic review and meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Pooled it
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- Trial
- Efficacy of sodium channel blockers in treating myotonia is independent of action potential sodium current block.The Journal of physiology · 2026Article
- Preclinical study of the antimyotonic efficacy of safinamide in the myotonic mouse model.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Molecular mechanisms and therapeutic strategies for neuromuscular diseases.Cellular and molecular life sciences : CMLS · 2024Review
- Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.EClinicalMedicine · 2024Article
- Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Functional cross-talk between phosphorylation and disease-causing mutations in the cardiac sodium channel NaProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Myotonic dystrophy type 1 drug development: A pipeline toward the market.Drug discovery today · 2021Review
- Article
- 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
- Article
- The Na conductance in the sarcolemma and the transverse tubular system membranes of mammalian skeletal muscle fibers.The Journal of general physiology · 2011Article
- Skeletal muscle na channel disorders.Frontiers in pharmacology · 2011Article
- A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia.Annals of neurology · 2009Article
- Bupivacaine blocks N-type inactivating Kv channels in the open state: no allosteric effect on inactivation kinetics.Biophysical journal · 2008Article
- Treatment of neuromuscular channelopathies: current concepts and future prospects.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2008Review
- Speeding the recovery from ultraslow inactivation of voltage-gated Na+ channels by metal ion binding to the selectivity filter: a foot-on-the-door?Biophysical journal · 2007Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
1. Over twenty different missense mutations in the alpha-subunit of the adult skeletal muscle Na(+) channel (hSkM1) have been identified as a cause of myotonia or periodic paralysis. We examined state-dependent mexiletine block for mutations involving the putative binding site in S6 segments (V445M, S804F, V1293I, V1589M and M1592V). Whole-cell Na(+) currents were measured from wild-type (WT) and mutant channels transiently expressed in HEK cells. 2. Use-dependent block (10 ms pulses to -10 mV, at 20 Hz) in 100 microM mexiletine was reduced modestly by mutations in IVS6 (V1589M, M1592V) and enhanced by the mutation in IS6 (V445M). For mutations in IIS6 (S804F) and IIIS6 (V1293I) use-dependent block was not statistically different from that of wild-type channels. 3. Resting-state block (10 ms pulses to -10 mV from -150 mV, at 0.1 Hz) of S6 mutants was comparable to that of WT (dissociation constant for resting channels, K(R) = 650 +/- 40 microM, n = 9). The S6 mutant with the greatest change in K(R) was V445M (K(R) = 794 +/- 45 microM, n = 5), but this difference was only marginally significant (P = 0.047). 4. A modified technique for estimating local anaesthetic affinity of inactivated channels was developed to reduce errors due to slow inactivation and to failure of drug binding to reach equilibrium. Mexiletine affinity for inactivated channels was reduced by mutations in IVS6 (V1589M: dissociation constant for the inactivated state (K(I)) = 44.7 microM; M1592V: K(I) = 40.0 microM) and increased by the mutation in IS6 (V445M: K(I) = 15.0 microM), compared to wild-type channels (K(I) = 28.3 microM). 5. We conclude that the disease-associated S6 mutations in domains I-IV cause at most a 2-fold change in inactivated state affinity and have even less of an effect on resting block. Model simulations show that the reduced use-dependent block of IVS6 mutants derives primarily from an increased off-rate at hyperpolarized potentials, whereas the enhanced use-dependent block of the IS6 mutant was due to a higher affinity for inactivated V445M channels.
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