title: Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency.
abstract: Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Kaiping
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China ; State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Baoxin
authors.initials: B
authors.lastname: Li
mesh_terms: D000200:Action Potentials; D001599:Berberine / Q000494:pharmacology*; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D009154:Mutation; D010649:Phenylalanine; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D034622:RNA Interference; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D016593:Terfenadine / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D013267:Stilbenes; D001599:Berberine; D014443:Tyrosine; D010649:Phenylalanine; D016593:Terfenadine; C093230:fexofenadine; D000077185:Resveratrol
keywords: LQTS; berberine; cardiotoxicity; cavoline-1; hERG; pharmacological rescue