ArticleProgress in biophysics and molecular biology2016
Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death.
Article in Progress in biophysics and molecular biology, 2016. 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, 20 citations in OpenAlex.
- The PAS domain directly regulates hERG channel gating in patch-clamp fluorometry recordings.Biophysical journal · 2026Article
- An ER retention motif controls the heteromeric stoichiometry of hERG1a/1b channels.bioRxiv : the preprint server for biology · 2026Article
- 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
- Molecular dynamics simulations suggest possible activation and deactivation pathways in the hERG channel.Communications biology · 2022Article
- Long QT syndrome - Bench to bedside.Heart rhythm O2 · 2021Article
- Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.Scientific reports · 2019Article
- Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart.Journal of cell science · 2018Article
- Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study.Frontiers in physiology · 2018Article
- hERG1a and hERG1b potassium channel subunits directly interact and preferentially form heteromeric channels.The Journal of biological chemistry · 2017Article
- A stable cell line inducibly expressing hERG1a/1b heteromeric channels.Journal of pharmacological and toxicological methodsArticle
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). Although the physiological importance of hERG 1b has been elucidated, the effects of hERG 1b disease mutations on cardiac IKr and AP behavior have not been described. To explore the disease mechanism of a 1b-specific mutation associated with a case of intrauterine fetal death, we examined the effects of the 1b-R25W mutation on total protein, trafficking and membrane current levels in HEK293 cells at physiological temperatures. By all measures the 1b-R25W mutation conferred diminished expression, and exerted a temperature-sensitive, dominant-negative effect over the WT hERG 1a protein with which it was co-expressed. Membrane currents were reduced by 60% with no apparent effect on voltage dependence or deactivation kinetics. The dominant-negative effects of R25W were demonstrated in iPSC-CMs, where 1b-R25W transfection diminished native IKr compared to controls. R25W also slowed AP repolarization, and increased AP triangulation and variability in iPSC-CMs, reflecting cellular manifestations of pro-arrhythmia. These data demonstrate that R25W is a dominant-negative mutation with significant pathophysiological consequences, and provide the first direct link between hERG 1b mutation and cardiomyocyte dysfunction.
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