Pharmacological rescue of mutated K(v)3.1 ion-channel linked to progressive myoclonus epilepsies

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Anders Sonne Munch, Arnela Saljic, Kim Boddum, Morten Grunnet, Charlotte Hougaard, Thomas Jespersen

Progressive myoclonus epilepsies (PMEs) constitute a cluster of inherent, genetically diverse, rare seizure disorders characterized by ataxia, tonic-clonic seizures, and action myoclonus. Recently, a mutation in the KCNC1 gene (Arg320His) was described in a group of PME patients. The KCNC1 gene encodes the K(v)3.1 potassium ion channel responsible for the rapid repolarization of the membrane potential following action potential firing in fast spiking GABAergic interneurons (FSI), thereby enabling high firing frequency. In the present study, we demonstrate that the Arg320His mutation cause a reduction in the K(v)3.1 current amplitude and acts in a dominantly negative fashion. The mutation profoundly affects channel activation and deactivation kinetics, and we further find that it impairs recruitment of the K(v)3.1 channel to the plasma membrane. The K(v)3 activating compound, RE01, partly rescues the electrophysiological deficit, suggesting that pharmacological activation of K(v)3.1 activity might be a feasible approach for treatment of this cohort of PME patients.
Original languageEnglish
JournalEuropean Journal of Pharmacology
Volume833
Pages (from-to)255-262
ISSN0014-2999
DOIs
Publication statusPublished - 2018

    Research areas

  • PME, K(v)3.1, MEAK, K(v)3 modulation, KCNC1, RE01, AUT 1

ID: 213153770