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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2023
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ftcdlib:oai:escholarship.org:ark:/13030/qt4ns8n9sv 2023-10-25T01:38:37+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 3281 2023-06-01 application/pdf https://escholarship.org/uc/item/4ns8n9sv unknown eScholarship, University of California qt4ns8n9sv https://escholarship.org/uc/item/4ns8n9sv public Nature Communications, vol 14, iss 1 Medical Physiology Biomedical and Clinical Sciences Genetics Brain Disorders Neurosciences Humans Ataxia Ion Channel Gating Kv1.1 Potassium Channel Mutation Indigenous Canadians Medicine Traditional article 2023 ftcdlib 2023-09-25T18:04:43Z 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 thatextracts 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. Article in Journal/Newspaper First Nations University of California: eScholarship Pacific |
institution |
Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Medical Physiology Biomedical and Clinical Sciences Genetics Brain Disorders Neurosciences Humans Ataxia Ion Channel Gating Kv1.1 Potassium Channel Mutation Indigenous Canadians Medicine Traditional |
spellingShingle |
Medical Physiology Biomedical and Clinical Sciences Genetics Brain Disorders Neurosciences Humans Ataxia Ion Channel Gating Kv1.1 Potassium Channel Mutation Indigenous Canadians Medicine Traditional 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 |
topic_facet |
Medical Physiology Biomedical and Clinical Sciences Genetics Brain Disorders Neurosciences Humans Ataxia Ion Channel Gating Kv1.1 Potassium Channel Mutation Indigenous Canadians Medicine Traditional |
description |
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 thatextracts 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 |
Article in Journal/Newspaper |
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 |
eScholarship, University of California |
publishDate |
2023 |
url |
https://escholarship.org/uc/item/4ns8n9sv |
op_coverage |
3281 |
geographic |
Pacific |
geographic_facet |
Pacific |
genre |
First Nations |
genre_facet |
First Nations |
op_source |
Nature Communications, vol 14, iss 1 |
op_relation |
qt4ns8n9sv https://escholarship.org/uc/item/4ns8n9sv |
op_rights |
public |
_version_ |
1780733701704908800 |