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Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency
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. T...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622489/ https://www.ncbi.nlm.nih.gov/pubmed/26543354 http://dx.doi.org/10.2147/DDDT.S91561 |
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author | Yan, Meng Zhang, Kaiping Shi, Yanhui Feng, Lifang Lv, Lin Li, Baoxin |
author_facet | Yan, Meng Zhang, Kaiping Shi, Yanhui Feng, Lifang Lv, Lin Li, Baoxin |
author_sort | Yan, Meng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4622489 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46224892015-11-05 Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency Yan, Meng Zhang, Kaiping Shi, Yanhui Feng, Lifang Lv, Lin Li, Baoxin Drug Des Devel Ther Original Research 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. Dove Medical Press 2015-10-22 /pmc/articles/PMC4622489/ /pubmed/26543354 http://dx.doi.org/10.2147/DDDT.S91561 Text en © 2015 Yan et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Yan, Meng Zhang, Kaiping Shi, Yanhui Feng, Lifang Lv, Lin Li, Baoxin Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title | Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title_full | Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title_fullStr | Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title_full_unstemmed | Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title_short | Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency |
title_sort | mechanism and pharmacological rescue of berberine-induced herg channel deficiency |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622489/ https://www.ncbi.nlm.nih.gov/pubmed/26543354 http://dx.doi.org/10.2147/DDDT.S91561 |
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