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Cell Rep. 2019 Jan 2;26(1):168-181.e4. doi: 10.1016/j.celrep.2018.12.032.

Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current.

Author information

1
Qingdao University School of Pharmacy, Qingdao 266021, China.
2
Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.
3
Qingdao University School of Pharmacy, Qingdao 266021, China; Institute of Innovative Drugs, Qingdao University School of Pharmacy, Qingdao 266071, China.
4
Department of Molecular and Cellular Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing 100191, China. Electronic address: ytang@mrc-lmb.cam.ac.uk.
5
Qingdao University School of Pharmacy, Qingdao 266021, China; Institute of Innovative Drugs, Qingdao University School of Pharmacy, Qingdao 266071, China. Electronic address: wangkw@qdu.edu.cn.

Abstract

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.

KEYWORDS:

A-type current; Hsp70; KChIP4a; Kv4; epilepsy; hyperexcitability; kainic acid; seizures; spontaneous recurrent seizures; status epilepticus

PMID:
30605673
DOI:
10.1016/j.celrep.2018.12.032
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