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Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

Authors Yan M, Zhang K, Shi Y, Feng L, Lv L, Li B

Received 1 July 2015

Accepted for publication 12 August 2015

Published 22 October 2015 Volume 2015:9 Pages 5737—5747

DOI https://doi.org/10.2147/DDDT.S91561

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Syed Nasir Abbas Bhukari

Peer reviewer comments 4

Editor who approved publication: Professor Shu-Feng Zhou


Meng Yan,1 Kaiping Zhang,1 Yanhui Shi,1 Lifang Feng,1 Lin Lv,1 Baoxin Li1,2

1Department of Pharmacology, Harbin Medical University, 2State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People’s Republic of China

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.

Keywords: berberine, hERG, cavoline-1, cardiotoxicity, LQTS, pharmacological rescue

Corrigendum for this paper has been published.

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