Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine.

Yang, Nien-Du; Kanyo, Richard; Zhao, Lu; Li, Jingru; Kang, Po Wei; Dou, Alex Kelly; White, Kelli McFarland; Shi, Jingyi; Nerbonne, Jeanne M; Kurata, Harley T; Cui, Jianmin

Yang, Nien-Du; Kanyo, Richard; Zhao, Lu; Li, Jingru; Kang, Po Wei; Dou, Alex Kelly; White, Kelli McFarland; Shi, Jingyi; Nerbonne, Jeanne M; Kurata, Harley T; Cui, Jianmin.

Afiliación

Yang ND; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
Kanyo R; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
Zhao L; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
Li J; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
Kang PW; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
Dou AK; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
White KM; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
Shi J; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.
Nerbonne JM; Departments of Developmental Biology and Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA.
Kurata HT; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
Cui J; Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA.

Sci Adv ; 8(29): eabo3625, 2022 Jul 22.

Article en En | MEDLINE | ID: mdl-35857840

RESUMEN

KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Risk_factors_studies Idioma: En Revista: Sci Adv Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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