Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bla...
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ftpubmed:oai:pubmedcentral.nih.gov:10244465 2023-07-02T03:32:16+02:00 Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain Manville, Rían W. Alfredo Freites, J. Sidlow, Richard Tobias, Douglas J. Abbott, Geoffrey W. 2023-06-06 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244465/ http://www.ncbi.nlm.nih.gov/pubmed/37280215 https://doi.org/10.1038/s41467-023-38834-6 en eng Nature Publishing Group UK http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244465/ http://www.ncbi.nlm.nih.gov/pubmed/37280215 http://dx.doi.org/10.1038/s41467-023-38834-6 © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . Nat Commun Article Text 2023 ftpubmed https://doi.org/10.1038/s41467-023-38834-6 2023-06-11T01:00:40Z There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies. Text First Nations PubMed Central (PMC) Pacific Nature Communications 14 1 |
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Article Manville, Rían W. Alfredo Freites, J. Sidlow, Richard Tobias, Douglas J. Abbott, Geoffrey W. Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
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There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies. |
format |
Text |
author |
Manville, Rían W. Alfredo Freites, J. Sidlow, Richard Tobias, Douglas J. Abbott, Geoffrey W. |
author_facet |
Manville, Rían W. Alfredo Freites, J. Sidlow, Richard Tobias, Douglas J. Abbott, Geoffrey W. |
author_sort |
Manville, Rían W. |
title |
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_short |
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_full |
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_fullStr |
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_full_unstemmed |
Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_sort |
native american ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
publisher |
Nature Publishing Group UK |
publishDate |
2023 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244465/ http://www.ncbi.nlm.nih.gov/pubmed/37280215 https://doi.org/10.1038/s41467-023-38834-6 |
geographic |
Pacific |
geographic_facet |
Pacific |
genre |
First Nations |
genre_facet |
First Nations |
op_source |
Nat Commun |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244465/ http://www.ncbi.nlm.nih.gov/pubmed/37280215 http://dx.doi.org/10.1038/s41467-023-38834-6 |
op_rights |
© The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
op_doi |
https://doi.org/10.1038/s41467-023-38834-6 |
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Nature Communications |
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