ArticleScientific reports2018
Investigating the state dependence of drug binding in hERG channels using a trapped-open channel phenotype.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- Mapping the avoid-ome: a systematic open-science approach to predictive ADMET.Nature communications · 2026Review
- Allosteric Mechanisms Underlying Long QT Syndrome Type 2 (LQT2)-Associated Mutations in hERG Channels.bioRxiv : the preprint server for biology · 2026Article
- Optimizing experimental designs for model selection of ion channel drug-binding mechanisms.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2025Article
- Inhibition of the hERG Potassium Channel by a Methanesulphonate-Free E-4031 Analogue.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Structural modeling of hERG channel-drug interactions using Rosetta.Frontiers in pharmacology · 2023Article
- Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome.Biophysical reviews · 2022Review
- Structural modeling of the hERG potassium channel and associated drug interactions.Frontiers in pharmacology · 2022Article
- Parallel Recordings of Transmembrane hERG Channel Currents Based on Solvent-Free Lipid Bilayer Microarray.Micromachines · 2021Article
- An Update on the Structure of hERG.Frontiers in pharmacology · 2019Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hERG channel is a key player in repolarization of the cardiac action potential. Pharmacological blockade of hERG channels depletes the cardiac repolarization reserve, increasing the risk of cardiac arrhythmias. The promiscuous nature of drug interactions with hERG presents a therapeutic challenge for drug design and development. Despite considerable effort, the mechanisms of drug binding remain incompletely understood. One proposed mechanism is that high-affinity drug binding preferentially occurs when channels are in the inactivated state. However, this has been difficult to test, since inactivation is rapid in hERG and access to the drug binding site is limited by slower opening of the activation gate. Here, we have directly assessed the role of inactivation in cisparide and terfenadine drug binding in mutant (I663P) hERG channels where the activation gate is trapped-open. We firstly demonstrate the utility of this approach by showing that inactivation, ion selectivity and high affinity drug binding are preserved in I663P mutant channels. We then assess the role of inactivation by applying cisapride and terfenadine at different membrane voltages, which induce varying degrees of inactivation. We show that the extent of block does not correlate with the extent of inactivation. These data suggest that inactivation is not a major determinant of cisapride or terfenadine binding in hERG channels.
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