ArticleDrug design, development and therapy2015
Mechanisms underlying probucol-induced hERG-channel deficiency.
Article in Drug design, development and therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- High-throughput in vitro screening and in silico analysis for Zika virus inhibitor identification.Scientific reports · 2025Article
- Probucol: revisiting as a multifaceted therapeutic agent in atherosclerosis.Frontiers in pharmacology · 2025Review
- Quercetin is a foe in the heart by targeting the hERG potassium channel.Iranian journal of basic medical sciences · 2024Article
- Evaluation of chronic drug-induced electrophysiological and cytotoxic effects using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Frontiers in pharmacology · 2023Article
- Toward a broader view of mechanisms of drug cardiotoxicity.Cell reports. Medicine · 2021Review
- Probucol treatment is associated with an ABCA1-independent mechanism of cholesterol efflux to lipid poor apolipoproteins from foam cell macrophages.BBA advances · 2021Article
- E3 Ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease.International journal of biological sciences · 2020Review
- Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities.International journal of molecular sciences · 2017Article
- 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
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (I Kr), which is important for cardiac repolarization. Reduction of I hERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes) or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on I hERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.
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