ArticleJournal of molecular and cellular cardiology2015
Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide.
Article in Journal of molecular and cellular cardiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 62 citations in OpenAlex.
- Article
- Intelligent in-cell electrophysiology: Reconstructing intracellular action potentials using a physics-informed deep learning model trained on nanoelectrode array recordings.Nature communications · 2025Article
- Harnessing Deep Learning Methods for Voltage-Gated Ion Channel Drug Discovery.Physiology (Bethesda, Md.) · 2025Review
- Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome.medRxiv : the preprint server for health sciences · 2024Article
- Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation.Science advances · 2024Article
- Article
- Store-Operated CaJournal of clinical medicine · 2023Review
- Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.Cardiovascular research · 2023Article
- Intracellular Binding of Terfenadine Competes with Its Access to Pancreatic ß-cell ATP-Sensitive KThe Journal of membrane biology · 2023Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- New Insights into Ion Channels: Predicting hERG-Drug Interactions.International journal of molecular sciences · 2022Article
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- Common Structural Pattern for Flecainide Binding in Atrial-Selective KPharmaceutics · 2022Article
- Conditional immortalization of human atrial myocytes for the generation of in vitro models of atrial fibrillation.Nature biomedical engineering · 2022Article
- Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips.Nature biomedical engineering · 2022Article
- The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia.Frontiers in physiology · 2022Review
- Electrophysiological and Proarrhythmic Effects of Hydroxychloroquine Challenge in Guinea-Pig Hearts.ACS pharmacology & translational science · 2021Article
- Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study.Journal of chemical information and modeling · 2021Article
- Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1.Frontiers in pharmacology · 2021Article
- Allosteric Coupling Between Drug Binding and the Aromatic Cassette in the Pore Domain of the hERG1 Channel: Implications for a State-Dependent Blockade.Frontiers in pharmacology · 2020Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded "hERG" potassium channels at clinically relevant concentrations. The aim of this study was to elucidate the underlying molecular basis of this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49μM and this was not significantly altered by reversing the direction of K(+) flux or raising external [K(+)]. The use of charged and uncharged flecainide analogues showed that the charged form of the drug accesses the channel from the cell interior to produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4-5 fold that of WT IhERG. The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6 helix (G648A, Y652A, F656A) mutations showed <10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s 27-fold and 142-fold their WT controls. Docking simulations using a MthK-based homology model suggested an allosteric effect of V625A, since in low energy conformations flecainide lay too low in the pore to interact directly with that residue. On the other hand, the molecule could readily form π-π stacking interactions with aromatic residues and particularly with F656. We conclude that flecainide accesses the hERG channel from the cell interior on channel gating, binding low in the inner cavity, with the S6 F656 residue acting as a principal binding determinant.
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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.