Bioelectricity Laboratory, Dept. of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.
Department of Chemistry, University of California, Irvine, CA, USA.
Nat Commun. 2023 Jun 6;14(1):3281. 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.
目前尚无已知药物可挽救导致遗传性运动障碍——发作性共济失调 1 型（EA1）的 Kv1.1 电压门控钾通道丧失功能序列变异的功能。西北太平洋夸扣特尔原住民使用 Fucus gardneri（藤壶海带）、Physocarpus capitatus（太平洋九节木）和 Urtica dioica（普通荨麻）来治疗运动性共济失调。在这里，我们表明这些植物的提取物增强了野生型 Kv1.1 电流，特别是在阈下电位下。对其成分的筛选表明，没食子酸和鞣酸同样增强了野生型 Kv1.1 电流，其效力为亚微摩尔。至关重要的是，提取物及其成分也增强了含有 EA1 相关序列变异的 Kv1.1 通道的活性。分子动力学模拟表明，没食子酸通过细胞外 S1-S2 连接子中的小分子结合位点增强 Kv1.1 活性。因此，传统的美洲原住民治疗共济失调的方法利用了一种分子机制基础，可以为治疗性纠正 EA1 提供信息，并且可能为其他 Kv1.1 相关通道病提供信息。
