ArticlePloS one2012
Action potential clamp and pharmacology of the variant 1 Short QT Syndrome T618I hERG K⁺ channel.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 27 citations in OpenAlex.
- Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide.Cellular and molecular life sciences : CMLS · 2024Article
- Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations.Open life sciences · 2023Article
- Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol.NPJ systems biology and applications · 2022Article
- Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation.Biochemical and biophysical research communications · 2022Article
- Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study.Frontiers in physiology · 2021Article
- Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1.Frontiers in pharmacology · 2020Article
- Functional and pharmacological characterization of an S5 domain hERG mutation associated with short QT syndrome.Heliyon · 2019Article
- Structural implications of hERG KThe Journal of biological chemistry · 2018Article
- Molecular Insights into the Short QT Syndrome.The Journal of innovations in cardiac rhythm management · 2018Article
- Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide.Journal of molecular and cellular cardiology · 2015Article
- Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.Investigative ophthalmology & visual science · 2013Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundThe familial Short QT Syndrome (SQTS) is associated with an increased risk of cardiac arrhythmia and sudden death. Gain-of-function mutations in the hERG K(+) channel protein have been linked to variant 1 of the SQTS. A hERG channel pore (T618I) mutation has recently been identified in families with heritable SQTS. This study aimed to determine effects of the T618I-hERG mutation on (i) hERG current (I(hERG)) elicited by ventricular action potentials; (ii) the sensitivity of I(hERG) to inhibition by four clinically used antiarrhythmic drugs.
methodsElectrophysiological recordings of I(hERG) were made at 37°C from HEK 293 cells expressing wild-type (WT) or T618I hERG. Whole-cell patch clamp recording was performed using both conventional voltage clamp and ventricular action potential (AP) clamp methods.
resultsUnder conventional voltage-clamp, WT I(hERG) peaked at 0-+10 mV, whilst for T618I I(hERG) maximal current was right-ward shifted to ∼ +40 mV. Voltage-dependent activation and inactivation of T618I I(hERG) were positively shifted (respectively by +15 and ∼ +25 mV) compared to WT I(hERG). The I(hERG) 'window' was increased for T618I compared to WT hERG. Under ventricular AP clamp, maximal repolarising WT I(hERG) occurred at ∼ -30 mV, whilst for T618I hERG peak I(hERG) occurred earlier during AP repolarisation, at ∼ +5 mV. Under conventional voltage clamp, half-maximal inhibitory concentrations (IC(50)) for inhibition of I(hERG) tails by quinidine, disopyramide, D-sotalol and flecainide for T618I hERG ranged between 1.4 and 3.2 fold that for WT hERG. Under action potential voltage clamp, T618I IC(50)s ranged from 1.2 to 2.0 fold the corresponding IC(50) values for WT hERG.
conclusionsThe T618I mutation produces a more modest effect on repolarising I(hERG) than reported previously for the N588K-hERG variant 1 SQTS mutation. All drugs studied here appear substantially to retain their ability to inhibit I(hERG) in the setting of the SQTS-linked T618I mutation.
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