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

Author:

Yang Nien-Du1ORCID,Kanyo Richard2ORCID,Zhao Lu1,Li Jingru2ORCID,Kang Po Wei1ORCID,Dou Alex Kelly1ORCID,White Kelli McFarland1ORCID,Shi Jingyi1,Nerbonne Jeanne M.3ORCID,Kurata Harley T.2ORCID,Cui Jianmin1ORCID

Affiliation:

1. 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.

2. Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.

3. Departments of Developmental Biology and Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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