Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yan, Meng, Zhang, Kaiping, Shi, Yanhui, Feng, Lifang, Lv, Lin, Li, Baoxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2015
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
_version_ 1782397596731441152
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
work_keys_str_mv AT yanmeng mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency
AT zhangkaiping mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency
AT shiyanhui mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency
AT fenglifang mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency
AT lvlin mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency
AT libaoxin mechanismandpharmacologicalrescueofberberineinducedhergchanneldeficiency