Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death.
Hyper-SUMOylation of the Kv7 potassium channel diminishes the M-current leading to seizures and sudden death.
复制标题
Kv7 钾通道的超 SUMO 化减少了导致癫痫发作和猝死的 M 电流
DOI：
10.1016/j.neuron.2014.07.042
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发表时间：
2014-09-03
期刊：
影响因子：
16.2
通讯作者：
Yeh ET
中科院分区：
文献类型：
--
作者：
Qi Y;Wang J;Bomben VC;Li DP;Chen SR;Sun H;Xi Y;Reed JG;Cheng J;Pan HL;Noebels JL;Yeh ET
癫痫中不明原因的猝死（SUDEP）是癫痫中过早死亡的最常见原因，与离子通道突变有关;然而，通道蛋白相互作用组中的基因也可能代表致病候选者。在这里，我们表明，部分缺乏Sentrin/SUMO特异性蛋白酶2（SENP 2）的小鼠发生自发性癫痫发作和猝死。SENP 2在海马体中高度富集，海马体通常是癫痫发作的焦点。SENP 2缺陷导致已知调节神经元兴奋性的多种钾通道的SUMO化过度。我们证明，由Kv 7通道进行的去极化M-电流显着减少SENP 2缺陷的海马CA 3神经元，主要负责神经元的过度兴奋。癫痫发作后，SENP 2缺陷小鼠出现房室传导阻滞和心脏停搏。癫痫发作和心脏传导阻滞都可以通过瑞替加滨（一种Kv 7通道开放剂）预防。因此，我们揭示了SUMO化在神经系统中的致病作用，并建立了SUDEP的动物模型。
Sudden unexplained death in epilepsy (SUDEP) is the most common cause of premature mortality in epilepsy and was linked to mutations in ion channels; however, genes within the channel protein interactome might also represent pathogenic candidates. Here we show that mice with partial deficiency of Sentrin/SUMO-specific protease 2 (SENP2) develop spontaneous seizures and sudden death. SENP2 is highly enriched in the hippocampus, often the focus of epileptic seizures. SENP2 deficiency results in hyper-SUMOylation of multiple potassium channels known to regulate neuronal excitability. We demonstrate that the depolarizing M-current conducted by Kv7 channel is significantly diminished in SENP2-deficient hippocampal CA3 neurons, primarily responsible for neuronal hyperexcitability. Following seizures, SENP2-deficient mice develop atrioventricular conduction blocks and cardiac asystole. Both seizures and cardiac conduction blocks can be prevented by retigabine, a Kv7 channel opener. Thus, we uncover a disease-causing role for hyper-SUMOylation in the nervous system and establish an animal model for SUDEP.