Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

• Published in: Nature communications 2023-06, Vol.14 (1), p.3281-3281, Article 3281
• Main Authors: Manville, Rían W., Alfredo Freites, J., Sidlow, Richard, Tobias, Douglas J., Abbott, Geoffrey W.
• Format: Article
• Language: English
• Subjects: 631/443; 631/45/269/1151; 631/57/2283; 631/92/436; 692/4017; Ataxia; Ataxia - drug therapy; Ataxia - genetics; Binding sites; Channels; Constituents; Drugs; Fucus gardneri; Gallic acid; Herbal medicine; Humanities and Social Sciences; Humans; Indigenous Canadians; Ion Channel Gating; Kv1.1 Potassium Channel - genetics; Kv1.1 Potassium Channel - metabolism; Medicinal plants; Medicine, Traditional; Minority & ethnic groups; Molecular dynamics; multidisciplinary; Mutants; Mutation; Physocarpus capitatus; Plant extracts; Potassium; Potassium channels (voltage-gated); Science; Science (multidisciplinary); Tannic acid; Urtica dioica
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38834-6

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. Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.