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

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: PubMed not MEDLINE; MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-

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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R01 GM104991 United States GM NIGMS NIH HHS; R01 HL126774 United States HL NHLBI NIH HHS; R01 HL142520 United States HL NHLBI NIH HHS

Date Created: 20220720 Latest Revision: 20240214

20240214

PMC9299555

10.1126/sciadv.abo3625

35857840