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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article numbereabo3625
JournalScience Advances
Volume8
Issue number29
DOIs
StatePublished - Jul 2022

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