ArticleCirculation research2008
Physiological properties of hERG 1a/1b heteromeric currents and a hERG 1b-specific mutation associated with Long-QT syndrome.
Article in Circulation research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 142 citations in OpenAlex.
- Sudden death-associated KCNH2 variants exert opposing effects on a nuclear subdomain of the cardiac potassium channel hERG1.The Journal of biological chemistry · 2026Article
- An ER retention motif controls the heteromeric stoichiometry of hERG1a/1b channels.bioRxiv : the preprint server for biology · 2026Article
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- High-throughput screens identify genotype-specific therapeutics for channelopathies.JCI insight · 2025Article
- Sudden Death-AssociatedbioRxiv : the preprint server for biology · 2025Article
- The air pollutant phenanthrene disrupts calcium cycling and alters repolarization in female sheep ventricular cardiomyocytes.Physiological reports · 2025Article
- A privileged ER compartment for posttranslational heteromeric assembly of an ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A privileged ER compartment for post-translational heteromeric assembly of an ion channel.bioRxiv : the preprint server for biology · 2025Article
- A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs.JCI insight · 2025Article
- Integrating drug effects on individual cardiac ionic currents and cardiac action potentials to understand nonclinical translation to clinical ECG changes.Frontiers in pharmacology · 2025Article
- Mechanistic Relevance of Ventricular Arrhythmias in Heart Failure with Preserved Ejection Fraction.International journal of molecular sciences · 2024Review
- An intracellular hydrophobic nexus critical for hERG1 channel slow deactivation.Biophysical journal · 2024Article
- Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript.Pflugers Archiv : European journal of physiology · 2024Article
- Pairwise biosynthesis of ion channels stabilizes excitability and mitigates arrhythmias.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- hERG1 channel subunit composition mediates proton inhibition of rapid delayed rectifier potassium current (IThe Journal of biological chemistry · 2023Article
- Article
- Hysteretic hERG channel gating current recorded at physiological temperature.Scientific reports · 2022Article
- Modeling the kinetics of heteromeric potassium channels.Frontiers in cellular neuroscience · 2022Article
- The ERG1 KFrontiers in molecular neuroscience · 2022Review
- Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant.Cellular and molecular life sciences : CMLS · 2021Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Cardiac I Kr is a critical repolarizing current in the heart and a target for inherited and acquired long-QT syndrome (LQTS). Biochemical and functional studies have demonstrated that I Kr channels are heteromers composed of both hERG 1a and 1b subunits, yet our current understanding of I Kr functional properties derives primarily from studies of homooligomers of the original hERG 1a isolate. Here, we examine currents produced by hERG 1a and 1a/1b channels expressed in HEK-293 cells at near-physiological temperatures. We find that heteromeric hERG 1a/1b currents are much larger than hERG 1a currents and conduct 80% more charge during an action potential. This surprising difference corresponds to a 2-fold increase in the apparent rates of activation and recovery from inactivation, thus reducing rectification and facilitating current rebound during repolarization. Kinetic modeling shows these gating differences account quantitatively for the differences in current amplitude between the 2 channel types. Drug sensitivity was also different. Compared to homomeric 1a channels, heteromeric 1a/1b channels were inhibited by E-4031 with a slower time course and a corresponding 4-fold shift in the IC50. The importance of hERG 1b in vivo is supported by the identification of a 1b-specific A8V missense mutation in 1/269 unrelated genotype-negative LQTS patients that was absent in 400 control alleles. Mutant 1bA8V expressed alone or with hERG 1a in HEK-293 cells dramatically reduced 1b protein levels. Thus, mutations specifically disrupting hERG 1b function are expected to reduce cardiac I Kr and enhance drug sensitivity, and represent a potential mechanism underlying inherited or acquired LQTS.
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