ArticleScientific reports2016
Role of the pH in state-dependent blockade of hERG currents.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk.International journal of molecular sciences · 2023Review
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- Mechanism of use-dependent Kv2 channel inhibition by RY785.The Journal of general physiology · 2022Article
- Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome.Biophysical reviews · 2022Review
- Lipid regulation of hERG1 channel function.Nature communications · 2021Article
- Refinement of a cryo-EM structure of hERG: Bridging structure and function.Biophysical journal · 2021Article
- pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology.Cancers · 2020Review
- Article
- A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm.Circulation research · 2020Article
- 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
- Drug-likeness of linear pentamidine analogues and their impact on the hERG KRSC advances · 2019Article
- The Pore-Lipid Interface: Role of Amino-Acid Determinants of Lipophilic Access by Ivabradine to the hERG1 Pore Domain.Molecular pharmacology · 2019Article
- Emerging Diversity in Lipid-Protein Interactions.Chemical reviews · 2019Review
- Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.Frontiers in pharmacology · 2018Article
- A multiscale computational modelling approach predicts mechanisms of female sex risk in the setting of arousal-induced arrhythmias.The Journal of physiology · 2017Article
- Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel.Scientific reports · 2017Article
- Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide's mode of action.
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Registered trials
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