ArticleProceedings of the National Academy of Sciences of the United States of America2010
Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 88 citations in OpenAlex.
- Polymorphic ventricular tachycardia with mutation in KCNJ2: case report.Frontiers in cardiovascular medicine · 2026Article
- Optogenetic quantification of cardiac excitability and electrical coupling in intact hearts to explain cardiac arrhythmia initiation.Science advances · 2025Article
- Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome.medRxiv : the preprint server for health sciences · 2024Article
- Mechanisms of Chemical Atrial Defibrillation by Flecainide and Ibutilide.JACC. Clinical electrophysiology · 2024Article
- The network of cardiac KNaunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Reply to Benndorff and DiFrancesco: Reliable human HCN4 single-channel recordings using the cell-attached configuration in expression systems.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Extracellular Kir2.1Circulation research · 2024Article
- A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- Extracellular cysteine disulfide bond break at Cys122 disrupts PIPbioRxiv : the preprint server for biology · 2023Article
- Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.Cardiovascular research · 2023Article
- Chronic Propafenone Application Increases Functional KPharmaceuticals (Basel, Switzerland) · 2023Article
- Precision medicine for long QT syndrome: patient-specific iPSCs take the lead.Expert reviews in molecular medicine · 2023Review
- A Cantú syndrome mutation produces dual effects on KATP channels by disrupting ankyrin B regulation.The Journal of general physiology · 2023Article
- Empagliflozin and Dapagliflozin Increase NaCells · 2022Article
- Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen-Tawil syndrome type 1.Nature cardiovascular research · 2022Article
- Tetramisole is a new IPharmacology research & perspectives · 2022Review
- Polyamines and Their Metabolism: From the Maintenance of Physiological Homeostasis to the Mediation of Disease.Medical sciences (Basel, Switzerland) · 2022Review
- Aminophylline at clinically relevant concentrations affects inward rectifier potassium current in a dual way.Pflugers Archiv : European journal of physiology · 2022Article
- Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.American journal of physiology. Cell physiology · 2021Review
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Both increase and decrease of cardiac inward rectifier current (I(K1)) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I(K1) (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I(Kir2.1)) and I(K1) recorded in ventricular myocytes. Flecainide increases outward I(Kir2.1) generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I(Kir2.2) and I(Kir2.3), because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.
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