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Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket
Epilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2–5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-curr...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155021/ https://www.ncbi.nlm.nih.gov/pubmed/30242262 http://dx.doi.org/10.1038/s41467-018-06339-2 |
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author | Manville, Rían W. Abbott, Geoffrey W. |
author_facet | Manville, Rían W. Abbott, Geoffrey W. |
author_sort | Manville, Rían W. |
collection | PubMed |
description | Epilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2–5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-current, which suppresses neuronal excitability, protecting against seizures. Here, in silico docking, mutagenesis and cellular electrophysiology reveal that two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Correspondingly, MTX and IVA combine to suppress pentylene tetrazole-induced tonic seizures in mice, whereas individually they are ineffective. Co-administering MTX and IVA with the modern, synthetic anticonvulsant retigabine creates a further synergy that voltage independently locks KCNQ2/3 open. Leveraging this synergy, which harnesses ancient and modern medicines to exploit differential KCNQ isoform preferences, presents an approach to developing safe yet effective anticonvulsants. |
format | Online Article Text |
id | pubmed-6155021 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61550212018-09-28 Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket Manville, Rían W. Abbott, Geoffrey W. Nat Commun Article Epilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2–5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-current, which suppresses neuronal excitability, protecting against seizures. Here, in silico docking, mutagenesis and cellular electrophysiology reveal that two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Correspondingly, MTX and IVA combine to suppress pentylene tetrazole-induced tonic seizures in mice, whereas individually they are ineffective. Co-administering MTX and IVA with the modern, synthetic anticonvulsant retigabine creates a further synergy that voltage independently locks KCNQ2/3 open. Leveraging this synergy, which harnesses ancient and modern medicines to exploit differential KCNQ isoform preferences, presents an approach to developing safe yet effective anticonvulsants. Nature Publishing Group UK 2018-09-21 /pmc/articles/PMC6155021/ /pubmed/30242262 http://dx.doi.org/10.1038/s41467-018-06339-2 Text en © The Author(s) 2018 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Manville, Rían W. Abbott, Geoffrey W. Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title | Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title_full | Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title_fullStr | Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title_full_unstemmed | Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title_short | Ancient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket |
title_sort | ancient and modern anticonvulsants act synergistically in a kcnq potassium channel binding pocket |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155021/ https://www.ncbi.nlm.nih.gov/pubmed/30242262 http://dx.doi.org/10.1038/s41467-018-06339-2 |
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