ArticleProceedings of the National Academy of Sciences of the United States of America2012
Modulation of hERG potassium channel gating normalizes action potential duration prolonged by dysfunctional KCNQ1 potassium channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Jervell and Lange-Nielsen Syndrome Related Clinical Genetics and Experimental Models.Pediatric discovery · 2026Review
- A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.JCI insight · 2025Article
- Creating cell-specific computational models of stem cell-derived cardiomyocytes using optical experiments.PLoS computational biology · 2024Article
- An Insight into the Potassium Currents of hERG and Their Simulation.Molecules (Basel, Switzerland) · 2023Article
- Building blocks of microphysiological system to model physiology and pathophysiology of human heart.Frontiers in physiology · 2023Review
- Pharmacological activation of the hERG KJournal of arrhythmia · 2022Review
- The ERG1 KFrontiers in molecular neuroscience · 2022Review
- Comparison of the Simulated Response of ThreeFrontiers in pharmacology · 2021Article
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- LUF7244, an allosteric modulator/activator of KBritish journal of pharmacology · 2019Article
- Action potential shortening rescues atrial calcium alternans.The Journal of physiology · 2019Article
- Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant.Journal of the American College of Cardiology · 2018Article
- Low Resting Membrane Potential and Low Inward Rectifier Potassium Currents Are Not Inherent Features of hiPSC-Derived Cardiomyocytes.Stem cell reports · 2018Article
- Structural Immaturity of Human iPSC-Derived Cardiomyocytes:Frontiers in physiology · 2018Article
- Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?British journal of pharmacology · 2017Review
- Modulation of KBritish journal of pharmacology · 2017Article
- Modification of distinct ion channels differentially modulates CaScientific reports · 2017Article
- The association between HERG gene expression and cardiac arrhythmia disease in children.Experimental and therapeutic medicine · 2016Article
- A new hERG allosteric modulator rescues genetic and drug-induced long-QT syndrome phenotypes in cardiomyocytes from isogenic pairs of patient induced pluripotent stem cells.EMBO molecular medicine · 2016Article
- Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice.Bioscience reports · 2016Article
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Authors and funding
13 authors at 6 institutions in 3 countries.
Funding
Abstract
Long QT syndrome (LQTS) is a genetic disease characterized by a prolonged QT interval in an electrocardiogram (ECG), leading to higher risk of sudden cardiac death. Among the 12 identified genes causal to heritable LQTS, ∼90% of affected individuals harbor mutations in either KCNQ1 or human ether-a-go-go related genes (hERG), which encode two repolarizing potassium currents known as I(Ks) and I(Kr). The ability to quantitatively assess contributions of different current components is therefore important for investigating disease phenotypes and testing effectiveness of pharmacological modulation. Here we report a quantitative analysis by simulating cardiac action potentials of cultured human cardiomyocytes to match the experimental waveforms of both healthy control and LQT syndrome type 1 (LQT1) action potentials. The quantitative evaluation suggests that elevation of I(Kr) by reducing voltage sensitivity of inactivation, not via slowing of deactivation, could more effectively restore normal QT duration if I(Ks) is reduced. Using a unique specific chemical activator for I(Kr) that has a primary effect of causing a right shift of V(1/2) for inactivation, we then examined the duration changes of autonomous action potentials from differentiated human cardiomyocytes. Indeed, this activator causes dose-dependent shortening of the action potential durations and is able to normalize action potentials of cells of patients with LQT1. In contrast, an I(Kr) chemical activator of primary effects in slowing channel deactivation was not effective in modulating action potential durations. Our studies provide both the theoretical basis and experimental support for compensatory normalization of action potential duration by a pharmacological agent.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.