University of Copenhagen, Faculty of Health Science, Department of Biomedical Sciences, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark; Synaptic Transmission In vitro, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
University of Copenhagen, Faculty of Health Science, Department of Biomedical Sciences, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Eur J Pharmacol. 2018 Aug 15;833:255-262. doi: 10.1016/j.ejphar.2018.06.015. Epub 2018 Jun 9.
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 K3.1 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 K3.1 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 K3.1 channel to the plasma membrane. The K3 activating compound, RE01, partly rescues the electrophysiological deficit, suggesting that pharmacological activation of K3.1 activity might be a feasible approach for treatment of this cohort of PME patients.
进行性肌阵挛性癫痫（PME）是一组固有、遗传多样、罕见的癫痫疾病，其特征为共济失调、强直阵挛性发作和动作性肌阵挛。最近，在一组 PME 患者中描述了 KCNC1 基因突变（Arg320His）。KCNC1 基因编码 K3.1 钾离子通道，负责在快速放电 GABA 能中间神经元（FSI）产生动作电位后快速复极化膜电位，从而实现高放电频率。在本研究中，我们证明 Arg320His 突变导致 K3.1 电流幅度减小，并以显性负性方式发挥作用。该突变深刻影响通道激活和失活动力学，我们进一步发现它会损害 K3.1 通道向质膜募集。K3 激活化合物 RE01 部分挽救了电生理学缺陷，表明 K3.1 活性的药理学激活可能是治疗这组 PME 患者的可行方法。
