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 (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.