A conifer metabolite corrects episodic ataxia type 1 by voltage sensor- mediated ligand activation of Kv1.1
成果类型：
Article
署名作者：
Manville, Rian W.; Foglia, Lorenzo; Yoshimura, Ryan F.; Hogenkamp, Derk J.; Nguyen, Amy; Yu, Alvin; Abbott, Geoffrey W.
署名单位：
University of California System; University of California Irvine; University of California System; University of California Irvine
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-14109
DOI：
10.1073/pnas.2411816122
发表日期：
2025-01-14
关键词：
chamaecyparis-pisifera
mutations
gene
mechanisms
channels
ponderosa
myokymia
diseases
摘要：
Loss- of- function sequence variants in KCNA1, which encodes the voltage- gated potassium channel Kv1.1, cause Episodic Ataxia Type 1 (EA1) and epilepsy. Due to a paucity of drugs that directly rescue mutant Kv1.1 channel function, current therapeutic strategies for KCNA1- linked disorders involve indirect modulation of neuronal excitability. Native Americans have traditionally used conifer extracts to treat paralysis, weakness, and pain, all of which may involve altered electrical activity and/or Kv1.1 dysfunction specifically. Here, screening conifer extracts, we found that Chamaecyparis pisifera increases wild- type (WT) Kv1.1 activity, as does its prominent metabolite, the abietane diterpenoid pisiferic acid. Uniquely, pisiferic acid also restored function in 12/12 EA1- linked mutant Kv1.1 channels tested in vitro. Crucially, pisiferic acid (1 mg/kg) restored WT function in Kv1.1E283K/+ mice, a model of human EA1. Experimentally validated all- atom molecular dynamics simulations in a neuron- like membrane revealed that the Kv1.1 voltage- sensing domain (VSD) also acts as a ligand- binding domain akin to those of classic ligand-gated channels; binding of pisiferic acid induces a conformational shift in the VSD that ligand- dependently opens the pore. Conifer metabolite pisiferic acid is a promising and versatile therapeutic lead for EA1 and other Kv1.1- linked disorders.