Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current
Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current
复制标题
抑制 Hsp70 可通过增强 A 型钾电流来抑制神经元过度兴奋并减轻癫痫
DOI：
10.1016/j.celrep.2018.12.032
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发表时间：
2019-01-02
期刊：
影响因子：
8.8
通讯作者：
Wang, KeWei
中科院分区：
文献类型：
--
作者：
Hu, Fang;Zhou, Jingheng;Wang, KeWei
热休克蛋白70（Hsp 70）在应激反应中上调，并被认为是颞叶癫痫（TLE）的应激标志物。然而，Hsp 70在TLE中是否发挥病理或保护作用仍不清楚。在这里，我们报告了有害的作用，热休克蛋白70在红藻氨酸（KA）诱导的癫痫发作。在颞叶癫痫的KA模型中，Hsp 70表达上调，沉默或抑制Hsp 70可通过增强海马神经元中的A型钾电流抑制神经元的过度兴奋性并减轻急性或慢性癫痫。Hsp 70上调导致主要编码神经元A型电流的Kv 4-KChIP 4a通道复合物的蛋白体降解。此外，Hsp 70直接结合到辅助KChIP 4a的N末端，并将Kv 4-KChIP 4a复合物靶向蛋白酶体。综上所述，我们的研究结果揭示了Hsp 70在癫痫发病机制中的作用，通过降解Kv 4-KChIP 4a复合物，Hsp 70的药理学抑制可能代表癫痫或过度兴奋相关的神经系统疾病的治疗潜力。
The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesis of epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.