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Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant
The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629796/ https://www.ncbi.nlm.nih.gov/pubmed/34727194 http://dx.doi.org/10.1007/s00018-021-03967-8 |
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author | Al-Moubarak, Ehab Shiels, Holly A. Zhang, Yihong Du, Chunyun Hanington, Oliver Harmer, Stephen C. Dempsey, Christopher E. Hancox, Jules C. |
author_facet | Al-Moubarak, Ehab Shiels, Holly A. Zhang, Yihong Du, Chunyun Hanington, Oliver Harmer, Stephen C. Dempsey, Christopher E. Hancox, Jules C. |
author_sort | Al-Moubarak, Ehab |
collection | PubMed |
description | The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the ability of phenanthrene to interact with hERG (human Ether-à-go-go-Related Gene) encoded Kv11.1 K(+) channels, which play a central role in human ventricular repolarization. Pharmacological inhibition of hERG can be proarrhythmic. Whole-cell patch clamp recordings of hERG current (I(hERG)) were made from HEK293 cells expressing wild-type (WT) and mutant hERG channels. WT I(hERG1a) was inhibited by phenanthrene with an IC(50) of 17.6 ± 1.7 µM, whilst I(hERG1a/1b) exhibited an IC(50) of 1.8 ± 0.3 µM. WT I(hERG) block showed marked voltage and time dependence, indicative of dependence of inhibition on channel gating. The inhibitory effect of phenanthrene was markedly impaired by the attenuated inactivation N588K mutation. Remarkably, mutations of S6 domain aromatic amino acids (Y652, F656) in the canonical drug binding site did not impair the inhibitory action of phenanthrene; the Y652A mutation augmented I(hERG) block. In contrast, the F557L (S5) and M651A (S6) mutations impaired the ability of phenanthrene to inhibit I(hERG), as did the S624A mutation below the selectivity filter region. Computational docking using a cryo-EM derived hERG structure supported the mutagenesis data. Thus, phenanthrene acts as an inhibitor of the hERG K(+) channel by directly interacting with the channel, binding to a distinct site in the channel pore domain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03967-8. |
format | Online Article Text |
id | pubmed-8629796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-86297962021-12-15 Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant Al-Moubarak, Ehab Shiels, Holly A. Zhang, Yihong Du, Chunyun Hanington, Oliver Harmer, Stephen C. Dempsey, Christopher E. Hancox, Jules C. Cell Mol Life Sci Original Article The lipophilic polycyclic aromatic hydrocarbon (PAH) phenanthrene is relatively abundant in polluted air and water and can access and accumulate in human tissue. Phenanthrene has been reported to interact with cardiac ion channels in several fish species. This study was undertaken to investigate the ability of phenanthrene to interact with hERG (human Ether-à-go-go-Related Gene) encoded Kv11.1 K(+) channels, which play a central role in human ventricular repolarization. Pharmacological inhibition of hERG can be proarrhythmic. Whole-cell patch clamp recordings of hERG current (I(hERG)) were made from HEK293 cells expressing wild-type (WT) and mutant hERG channels. WT I(hERG1a) was inhibited by phenanthrene with an IC(50) of 17.6 ± 1.7 µM, whilst I(hERG1a/1b) exhibited an IC(50) of 1.8 ± 0.3 µM. WT I(hERG) block showed marked voltage and time dependence, indicative of dependence of inhibition on channel gating. The inhibitory effect of phenanthrene was markedly impaired by the attenuated inactivation N588K mutation. Remarkably, mutations of S6 domain aromatic amino acids (Y652, F656) in the canonical drug binding site did not impair the inhibitory action of phenanthrene; the Y652A mutation augmented I(hERG) block. In contrast, the F557L (S5) and M651A (S6) mutations impaired the ability of phenanthrene to inhibit I(hERG), as did the S624A mutation below the selectivity filter region. Computational docking using a cryo-EM derived hERG structure supported the mutagenesis data. Thus, phenanthrene acts as an inhibitor of the hERG K(+) channel by directly interacting with the channel, binding to a distinct site in the channel pore domain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-021-03967-8. Springer International Publishing 2021-11-02 2021 /pmc/articles/PMC8629796/ /pubmed/34727194 http://dx.doi.org/10.1007/s00018-021-03967-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Al-Moubarak, Ehab Shiels, Holly A. Zhang, Yihong Du, Chunyun Hanington, Oliver Harmer, Stephen C. Dempsey, Christopher E. Hancox, Jules C. Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title | Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title_full | Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title_fullStr | Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title_full_unstemmed | Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title_short | Inhibition of the hERG potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
title_sort | inhibition of the herg potassium channel by phenanthrene: a polycyclic aromatic hydrocarbon pollutant |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629796/ https://www.ncbi.nlm.nih.gov/pubmed/34727194 http://dx.doi.org/10.1007/s00018-021-03967-8 |
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