M-Calpain Activation Facilitates Seizure Induced KCC2 Down Regulation.
M-Calpain Activation Facilitates Seizure Induced KCC2 Down Regulation.
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M-钙蛋白酶激活促进癫痫发作诱导的 KCC2 下调
DOI：
10.3389/fnmol.2018.00287
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发表时间：
2018
影响因子：
4.8
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Wan L;Ren L;Chen L;Wang G;Liu X;Wang BH;Wang Y
氯化钾协同转运体2(KCC2)是一种主要的氯离子转运体，在成熟的哺乳动物神经元中维持GABAA受体的抑制，在癫痫发生过程中在海马区表达下调。KCC2功能受损可加速或促进癫痫发作。钙蛋白酶是一种钙离子依赖的半胱氨酸蛋白酶，主要有m-和μ-钙蛋白酶两种亚型，可介导KCC2的非溶酶体降解。尽管最近的研究表明，Calain抑制剂在急性和慢性癫痫动物模型中具有抗癫痫和神经保护作用，但Calain的激活是否通过KCC2的降解影响癫痫的诱导仍不清楚。结果表明：(1)非选择性钙激活酶抑制剂MDL-28170阻断钙激活酶可抑制惊厥刺激引起的KCC2表达下调，降低戊四氮致痫的发生率和严重程度。(2)m-calain，而不是μ-calain，其抑制KCC2下调的作用与mdl-28170相似。(3)在癫痫发作过程中，m-calain的磷酸化显著增强，这部分是通过激活非钙依赖的MAPK/ERK信号通路来实现的。(4)阻断MAPK/ERK信号通路对KCC2的下调和对动物惊厥的诱导作用与钙蛋白完全阻断的作用相似。结果表明，在惊厥刺激过程中，MAPK/ERK上调m-calain的激活，下调胞浆和胞膜KCC2的表达，进而促进癫痫的诱发。这一发现可能为开发以m-calain为靶点的高效抗癫痫药物奠定基础。
Potassium chloride co-transporter 2 (KCC2), a major chloride transporter that maintains GABAA receptor inhibition in mature mammalian neurons, is down-regulated in the hippocampus during epileptogenesis. Impaired KCC2 function accelerates or facilitates seizure onset. Calpain, with two main subtypes of m- and μ-calpain, is a Ca2+-dependent cysteine protease that mediates the nonlysosomal degradation of KCC2. Although recent studies have demonstrated that calpain inhibitors exert antiepileptic and neuroprotective effects in animal models of acute and chronic epilepsy, whether calpain activation affects seizure induction through KCC2 degradation remains unknown. Our results showed that: (1) Blockade of calpain by non-selective calpain inhibitor MDL-28170 prevented convulsant stimulation induced KCC2 downregulation, and reduced the incidence and the severity of pentylenetetrazole (PTZ) induced seizures. (2) m-calpain, but not μ-calpain, inhibitor mimicked MDL-28170 effect on preventing KCC2 downregulation. (3) Phosphorylation of m-calpain has been significantly enhanced during seizure onset, which was partly mediated by the calcium independent MAPK/ERK signaling pathway activation. (4) MAPK/ERK signaling blockade also had similar effect as total calpain blockade on both KCC2 downregulation and animal seizure induction. The results indicate that upregulated m-calpain activation by MAPK/ERK during convulsant stimulation down regulates both cytoplasm- and membrane KCC2, and in turn facilitates seizure induction. This finding may provide a foundation for the development of highly effective antiepileptic drugs targeting of m-calpain.
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影响因子：
5.3
作者：
Chamma I;Chevy Q;Poncer JC;Lévi S
通讯作者：
Lévi S
影响因子：
4.2
作者：
Baek, Hyunjung;Yi, Min-Hee;Kang, Joon Won
通讯作者：
Kang, Joon Won
影响因子：
5.3
作者：
Glading, A;Bodnar, RJ;Wells, A
通讯作者：
Wells, A
DOI：
10.12659/msm.897579
发表时间：
2016-11-17
期刊：
Medical science monitor : international medical journal of experimental and clinical research
影响因子：
--
作者：
Hao F;Jia LH;Li XW;Zhang YR;Liu XW
通讯作者：
Liu XW
影响因子：
5.6
作者：
Kahle, Kristopher T.;Khanna, Arjun R.;Poduri, Annapurna
通讯作者：
Poduri, Annapurna