ArticleThe Journal of biological chemistry2012
Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 62 citations in OpenAlex.
- Targeting the Ubiquitin-Proteasome System in Atrial Fibrillation: Mechanistic Insights and Translational Perspectives.Current issues in molecular biology · 2025Review
- The proteostasis interactomes of trafficking-deficient variants of the voltage-gated potassium channel KThe Journal of biological chemistry · 2024Article
- Diversity of cells and signals in the cardiovascular system.The Journal of physiology · 2023Article
- The cellular pathways that maintain the quality control and transport of diverse potassium channels.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
- Review
- Article
- Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy.Frontiers in pharmacology · 2022Article
- Antiviral and anti-inflammatory drugs to combat COVID-19: Effects on cardiac ion channels and risk of ventricular arrhythmias.BioImpacts : BI · 2022Review
- The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.International journal of molecular sciences · 2021Review
- Mechanisms of Cav3-associated arrhythmia: Protein or microdomain dysfunction?International journal of cardiology · 2020Article
- Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy.American journal of physiology. Gastrointestinal and liver physiology · 2020Article
- LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase.Circulation. Genomic and precision medicine · 2019Article
- Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression.Scientific reports · 2019Article
- Trafficking of the human ether-a-go-go-related gene (hERG) potassium channel is regulated by the ubiquitin ligase rififylin (RFFL).The Journal of biological chemistry · 2019Article
- Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation.Oncotarget · 2017Article
- An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities.International journal of molecular sciences · 2017Article
- The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1.Development (Cambridge, England) · 2017Article
- hERG quality control and the long QT syndrome.The Journal of physiology · 2016Review
- The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels.Scientific reports · 2015Article
- Microdomain-specific localization of functional ion channels in cardiomyocytes: an emerging concept of local regulation and remodelling.Biophysical reviews · 2015Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (I(Kr)) which plays an important role in cardiac repolarization. A reduction or increase in hERG current can cause long or short QT syndrome, respectively, leading to fatal cardiac arrhythmias. The channel density in the plasma membrane is a key determinant of the whole cell current amplitude. To gain insight into the molecular mechanisms for the regulation of hERG density at the plasma membrane, we used whole cell voltage clamp, Western blotting, and immunocytochemical methods to investigate the effects of an integral membrane protein, caveolin-3 (Cav3) on hERG expression levels. Our data demonstrate that Cav3, hERG, and ubiquitin-ligase Nedd4-2 interact with each other and form a complex. Expression of Cav3 thus enhances the hERG-Nedd4-2 interaction, leading to an increased ubiquitination and degradation of mature, plasma-membrane localized hERG channels. Disrupting Nedd4-2 interaction with hERG by mutations eliminates the effects of Cav3 on hERG channels. Knockdown of endogenous Cav3 or Nedd4-2 in cultured neonatal rat ventricular myocytes using siRNA led to an increase in native I(Kr). Our data demonstrate that hERG expression in the plasma membrane is regulated by Cav3 via Nedd4-2. These findings extend our understanding of the regulation of hERG channels and cardiac electrophysiology.
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