ArticleMolecular pharmacology2011
Molecular determinants for activation of human ether-à-go-go-related gene 1 potassium channels by 3-nitro-n-(4-phenoxyphenyl) benzamide.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Molecular insights into the rescue mechanism of an HERG activator against severe LQT2 mutations.Journal of biomedical science · 2025Article
- An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.BMC biology · 2024Article
- Unexpected impairment ofNature cardiovascular research · 2023Article
- The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels.Frontiers in pharmacology · 2021Article
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3.Molecular pharmacology · 2017Article
- Modulation of KBritish journal of pharmacology · 2017Article
- Ginsenoside Rg3, a Gating Modifier of EAG Family K+ Channels.Molecular pharmacology · 2016Article
- Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.Cardiac electrophysiology clinics · 2016Review
- New potential binding determinant for hERG channel inhibitors.Scientific reports · 2016Article
- Drug trapping in hERG KMedChemComm · 2016Article
- Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel.British journal of pharmacology · 2015Article
- Concatenated hERG1 tetramers reveal stoichiometry of altered channel gating by RPR-260243.Molecular pharmacology · 2015Article
- Cooperative subunit interactions mediate fast C-type inactivation of hERG1 K+ channels.The Journal of physiology · 2014Article
- HERG1 channel agonists and cardiac arrhythmia.Current opinion in pharmacology · 2014Review
- Stoichiometry of altered hERG1 channel gating by small molecule activators.The Journal of general physiology · 2014Article
- Structure driven design of novel human ether-a-go-go-related-gene channel (hERG1) activators.PloS one · 2014Article
- ICA-105574 interacts with a common binding site to elicit opposite effects on inactivation gating of EAG and ERG potassium channels.Molecular pharmacology · 2013Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Human ether-à-go-go-related gene 1 (hERG1) channels mediate repolarization of cardiac action potentials. Inherited long QT syndrome (LQTS) caused by loss-of-function mutations, or unintended blockade of hERG1 channels by many drugs, can lead to severe arrhythmia and sudden death. Drugs that activate hERG1 are a novel pharmacological approach to treat LQTS. 3-Nitro-n-(4-phenoxyphenyl) benzamide [ICA-105574 (ICA)] has been discovered to activate hERG1 by strong attenuation of pore-type inactivation. Here, we used scanning mutagenesis of hERG1 to identify the molecular determinants of ICA action. Three mutations abolished the activator effects of 30 μM ICA, including L622C in the pore helix, F557L in the S5 segment, and Y652A in the S6 segment. One mutation in S6 (A653M) switched the activity of ICA from an activator to an inhibitor, revealing its partial agonist activity. This was confirmed by showing that the noninactivating mutant hERG1 channel (G628C/S631C) was inhibited by ICA and that the addition of the F557L mutation rendered the channel drug-insensitive. Simulated molecular docking of ICA to homology models of hERG1 corroborated the scanning mutagenesis findings. Together, our findings indicate that ICA is a mixed agonist of hERG1 channels. Activation or inhibition of currents is mediated by the same or overlapping binding site located in the pore module between two adjacent subunits of the homotetrameric channel.
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