ArticleThe Journal of biological chemistry2011
Antidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Computational modelling of the pro- and antiarrhythmic effects of atrial high rate-dependent trafficking of small-conductance calcium-activated potassium channels.The Journal of physiology · 2026Article
- In silico analysis of the dynamic regulation of cardiac electrophysiology by KThe Journal of physiology · 2023Article
- Inhibition of TRPC4 channel activity in colonic myocytes by tricyclic antidepressants disrupts colonic motility causing constipation.Journal of cellular and molecular medicine · 2022Article
- Review
- Toward a broader view of mechanisms of drug cardiotoxicity.Cell reports. Medicine · 2021Review
- Review
- Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation.Oxidative medicine and cellular longevity · 2020Article
- Mitragynine, an euphoric compound inhibits hERG1a/1b channel current and upregulates the complexation of hERG1a-Hsp90 in HEK293-hERG1a/1b cells.Scientific reports · 2019Article
- Drug-induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias.British journal of pharmacology · 2019Article
- Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression.Scientific reports · 2019Article
- Suppression of hERG KRedox biology · 2018Article
- Development of a High-Throughput Flow Cytometry Assay to Monitor Defective Trafficking and Rescue of Long QT2 Mutant hERG Channels.Frontiers in physiology · 2018Article
- Unexpected Efficacy of a Novel Sodium Channel Modulator in Dravet Syndrome.Scientific reports · 2017Article
- Article
- Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning.Journal of psychopharmacology (Oxford, England) · 2017Article
- Molecular pathogenesis of long QT syndrome type 2.Journal of arrhythmia · 2016Review
- Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect.International journal of molecular sciences · 2016Article
- Life-threatening cardiac arrhythmias due to drug-induced QT prolongation : A retrospective study over 6 years from a medical intensive care unit.Medizinische Klinik, Intensivmedizin und Notfallmedizin · 2016Article
- hERG quality control and the long QT syndrome.The Journal of physiology · 2016Review
- Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency.Drug design, development and therapy · 2015Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The most common cause for adverse cardiac events by antidepressants is acquired long QT syndrome (acLQTS), which produces electrocardiographic abnormalities that have been associated with syncope, torsade de pointes arrhythmias, and sudden cardiac death. acLQTS is often caused by direct block of the cardiac potassium current I(Kr)/hERG, which is crucial for terminal repolarization in human heart. Importantly, desipramine belongs to a group of tricyclic antidepressant compounds that can simultaneously block hERG and inhibit its surface expression. Although up to 40% of all hERG blockers exert combined hERG block and trafficking inhibition, few of these compounds have been fully characterized at the cellular level. Here, we have studied in detail how desipramine inhibits hERG surface expression. We find a previously unrecognized combination of two entirely different mechanisms; desipramine increases hERG endocytosis and degradation as a consequence of drug-induced channel ubiquitination and simultaneously inhibits hERG forward trafficking from the endoplasmic reticulum. This unique combination of cellular effects in conjunction with acute channel block may explain why tricyclic antidepressants as a compound class are notorious for their association with arrhythmias and sudden cardiac death. Taken together, we describe the first example of drug-induced channel ubiquitination and degradation. Our data are directly relevant to the cardiac safety of not only tricyclic antidepressants but also other therapeutic compounds that exert multiple effects on hERG, as hERG trafficking and degradation phenotypes may go undetected in most preclinical safety assays designed to screen for acLQTS.
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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.