ArticleBritish journal of pharmacology2008
Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome.
Article in British journal of pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 80 citations in OpenAlex.
- Trial
- Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis.AIDS (London, England) · 2018Trial
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.Molecular biology reports · 2024Article
- Toward a broader view of mechanisms of drug cardiotoxicity.Cell reports. Medicine · 2021Review
- Cardiac hERG KHandbook of experimental pharmacology · 2021Article
- Cardiac Potassium Channels: Physiological Insights for Targeted Therapy.Journal of cardiovascular pharmacology and therapeutics · 2018Review
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- hERG quality control and the long QT syndrome.The Journal of physiology · 2016Review
- Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias.Current cardiology reviews · 2016Review
- The Role of Interaction Model in Simulation of Drug Interactions and QT Prolongation.Current pharmacology reports · 2016Review
- Ubiquitination-dependent quality control of hERG K+ channel with acquired and inherited conformational defect at the plasma membrane.Molecular biology of the cell · 2013Article
- Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.British journal of pharmacology · 2013Article
- Inside job: ligand-receptor pharmacology beneath the plasma membrane.Acta pharmacologica Sinica · 2013Review
- Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K(+) channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells.British journal of pharmacology · 2013Article
- Molecular determinants of pentamidine-induced hERG trafficking inhibition.Molecular pharmacology · 2012Article
- Antidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG.The Journal of biological chemistry · 2011Article
- Impact of ABCB1 allelic variants on QTc interval prolongation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2011Article
- hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine.Naunyn-Schmiedeberg's archives of pharmacology · 2011Article
- Ion channel trafficking: a new therapeutic horizon for atrial fibrillation.Heart rhythm · 2010Review
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeMany drugs associated with acquired long QT syndrome (LQTS) directly block human ether-a-go-go-related gene (hERG) K(+) channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein. EXPERIMENTAL APPROACH: Wild-type hERG and SCN5A/hNa(v) 1.5 Na(+) channels or the Y652A and F656C mutated forms of the hERG were stably expressed in HEK293 cells. The K(+) and Na(+) currents were recorded in these cells by using the whole-cell patch-clamp technique (23 degrees C). Protein trafficking of the hERG was evaluated by Western blot analysis and flow cytometry. KEY
resultsKetoconazole directly blocked the hERG channel current and reduced the amount of hERG channel protein trafficked to the cell surface in a concentration-dependent manner. Current density of the hERG channels but not of the hNa(v) 1.5 channels was reduced after 48 h of incubation with ketoconazole, with preservation of the acute direct effect on hERG current. Mutations in drug-binding sites (F656C or Y652A) of the hERG channel significantly attenuated the hERG current blockade by ketoconazole, but did not affect the disruption of trafficking. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that ketoconazole might cause acquired LQTS via a direct inhibition of current through the hERG channel and by disrupting hERG protein trafficking within therapeutic concentrations. These findings should be considered when evaluating new drugs.
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