ArticleJournal of molecular and cellular cardiology2014
Ranolazine inhibition of hERG potassium channels: drug-pore interactions and reduced potency against inactivation mutants.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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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
30 citing papers in PubMed, 52 citations in OpenAlex.
- Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide.Cellular and molecular life sciences : CMLS · 2024Article
- Calculations of the binding free energies of the ComprehensiveBiophysics and physicobiology · 2023Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome.International journal of molecular sciences · 2022Article
- Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.Clinical and translational medicine · 2021Review
- Article
- Asymmetric Interplay Between KFrontiers in physiology · 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
- A structure-based computational workflow to predict liability and binding modes of small molecules to hERG.Scientific reports · 2020Article
- Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man.Frontiers in pharmacology · 2020Article
- Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.Scientific reports · 2019Article
- Calculation of absolute binding free energies between the hERG channel and structurally diverse drugs.Scientific reports · 2019Article
- Heterogeneity of the action potential duration is required for sustained atrial fibrillation.JCI insight · 2019Article
- Article
- Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels.Frontiers in pharmacology · 2019Article
- An Update on the Structure of hERG.Frontiers in pharmacology · 2019Review
- Cardiovascular pharmacology of KNaunyn-Schmiedeberg's archives of pharmacology · 2018Article
- Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome.Physiological reports · 2018Article
- Structural implications of hERG KThe Journal of biological chemistry · 2018Article
- Probing the molecular basis of hERG drug block with unnatural amino acids.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03μM; peak IhERG during ventricular action potential clamp was inhibited ~62% at 10μM. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively ~73-fold and ~15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K(+) flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients.
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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.