Source data: 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...
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ftzenodo:oai:zenodo.org:7908428 2024-09-15T18:06:44+00:00 Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain Manville, Rían Abbott, Geoffrey 2023-05-26 https://doi.org/10.7280/D1569B unknown Zenodo https://zenodo.org/communities/dryad https://doi.org/10.7280/D1569B oai:zenodo.org:7908428 info:eu-repo/semantics/openAccess Creative Commons Zero v1.0 Universal https://creativecommons.org/publicdomain/zero/1.0/legalcode info:eu-repo/semantics/other 2023 ftzenodo https://doi.org/10.7280/D1569B 2024-07-26T00:57:30Z 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, extracts of these plants enhanced wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augmented wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhanced activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations revealed that gallic acid augments Kv1.1 activity via a previously unreported 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. Funding provided by: National Institute of General Medical Sciences Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000057 Award Number: GM130377 Other/Unknown Material First Nations Zenodo |
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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, extracts of these plants enhanced wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augmented wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhanced activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations revealed that gallic acid augments Kv1.1 activity via a previously unreported 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. Funding provided by: National Institute of General Medical Sciences Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000057 Award Number: GM130377 |
format |
Other/Unknown Material |
author |
Manville, Rían Abbott, Geoffrey |
spellingShingle |
Manville, Rían Abbott, Geoffrey Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
author_facet |
Manville, Rían Abbott, Geoffrey |
author_sort |
Manville, Rían |
title |
Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_short |
Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_full |
Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_fullStr |
Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_full_unstemmed |
Source data: Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
title_sort |
source data: native american ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain |
publisher |
Zenodo |
publishDate |
2023 |
url |
https://doi.org/10.7280/D1569B |
genre |
First Nations |
genre_facet |
First Nations |
op_relation |
https://zenodo.org/communities/dryad https://doi.org/10.7280/D1569B oai:zenodo.org:7908428 |
op_rights |
info:eu-repo/semantics/openAccess Creative Commons Zero v1.0 Universal https://creativecommons.org/publicdomain/zero/1.0/legalcode |
op_doi |
https://doi.org/10.7280/D1569B |
_version_ |
1810444114696601600 |