ArticleThe Journal of general physiology2014
Stoichiometry of altered hERG1 channel gating by small molecule activators.
Article in The Journal of general physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Gene arrangement within concatemeric constructs governs the functional divergence of human and rat ASIC3 concatemers.Journal of physiology and biochemistry · 2026Article
- Molecular insights into the rescue mechanism of an HERG activator against severe LQT2 mutations.Journal of biomedical science · 2025Article
- Binding of RPR260243 at the intracellular side of the hERG1 channel pore domain slows closure of the helix bundle crossing gate.Frontiers in molecular biosciences · 2023Article
- Pharmacological activation of the hERG KJournal of arrhythmia · 2022Review
- Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics.Frontiers in pharmacology · 2021Review
- Investigating the utility of adult zebrafish ex vivo whole hearts to pharmacologically screen hERG channel activator compounds.American journal of physiology. Regulatory, integrative and comparative physiology · 2019Article
- An Update on the Structure of hERG.Frontiers in pharmacology · 2019Review
- Molecular Basis of Altered hERG1 Channel Gating Induced by Ginsenoside Rg3.Molecular pharmacology · 2017Article
- Antiarrhythmics cure brain arrhythmia: The imperativeness of subthalamic ERG KScience advances · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Ginsenoside Rg3, a Gating Modifier of EAG Family K+ Channels.Molecular pharmacology · 2016Article
- Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.Cardiac electrophysiology clinics · 2016Review
- Intersubunit Concerted Cooperative and cis-Type Mechanisms Modulate Allosteric Gating in Two-Pore-Domain Potassium Channel TREK-2.Frontiers in cellular neuroscience · 2016Article
- C-Linker Accounts for Differential Sensitivity of ERG1 and ERG2 K+ Channels to RPR260243-Induced Slow Deactivation.Molecular pharmacology · 2015Article
- The Link between Inactivation and High-Affinity Block of hERG1 Channels.Molecular 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
- Can many subunits make light work of ion channel inactivation?The Journal of physiology · 2014Article
- Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Voltage-gated K(+) channels are tetramers formed by coassembly of four identical or highly related subunits. All four subunits contribute to formation of the selectivity filter, the narrowest region of the channel pore which determines K(+) selective conductance. In some K(+) channels, the selectivity filter can undergo a conformational change to reduce K(+) flux by a mechanism called C-type inactivation. In human ether-a-go-go-related gene 1 (hERG1) K(+) channels, C-type inactivation is allosterically inhibited by ICA-105574, a substituted benzamide. PD-118057, a 2-(phenylamino) benzoic acid, alters selectivity filter gating to enhance open probability of channels. Both compounds bind to a hydrophobic pocket located between adjacent hERG1 subunits. Accordingly, a homotetrameric channel contains four identical activator binding sites. Here we determine the number of binding sites required for maximal drug effect and determine the role of subunit interactions in the modulation of hERG1 gating by these compounds. Concatenated tetramers were constructed to contain a variable number (zero to four) of wild-type and mutant hERG1 subunits, either L646E to inhibit PD-118057 binding or F557L to inhibit ICA-105574 binding. Enhancement of hERG1 channel current magnitude by PD-118057 and attenuated inactivation by ICA-105574 were mediated by cooperative subunit interactions. Maximal effects of the both compounds required the presence of all four binding sites. Understanding how hERG1 agonists allosterically modify channel gating may facilitate mechanism-based drug design of novel agents for treatment of long QT syndrome.
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