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Mechanisms underlying probucol-induced hERG-channel deficiency
Yuan-Qi Shi1, Cai-Chuan Yan1, Xiao Zhang1
1Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
Drug Design, Development and Therapy
|August 1, 2015
Summary
Probucol reduces cardiac hERG channel expression by decreasing SGK1, leading to potential long QT syndrome. Carbachol may counteract this effect, offering a potential treatment for probucol cardiotoxicity.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Drug Safety
Background:
- The hERG gene is crucial for cardiac repolarization.
- Reduced hERG current causes long QT syndrome and life-threatening arrhythmias.
- Probucol, a cholesterol-lowering drug, can decrease hERG current and protein expression.
Purpose of the Study:
- To investigate the molecular mechanisms underlying probucol's effects on hERG channel expression and function.
- To elucidate how probucol impacts hERG protein levels and cardiac repolarization.
Main Methods:
- Concentration-dependent analysis of probucol's effect on hERG expression.
- Assessment of SGK1 and Nedd4-2 (total and phosphorylated) levels.
- Investigation of carbachol's potential to rescue probucol-induced hERG channel deficiency.
Main Results:
- Probucol reduces SGK1 expression, leading to decreased phosphorylation of Nedd4-2.
- This results in enhanced ubiquitination and subsequent degradation of hERG protein.
- Carbachol enhances Nedd4-2 phosphorylation, rescuing hERG channels from probucol-induced degradation.
Conclusions:
- Probucol induces hERG channel deficiency through a novel SGK1/Nedd4-2 pathway.
- Carbachol or its analogs may offer a therapeutic strategy against probucol cardiotoxicity.
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