Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis
Rapamycin reveals an mTOR-independent repression of Kv1.1 expression during epileptogenesis
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雷帕霉素揭示癫痫发生过程中 Kv1.1 表达的不依赖于 mTOR 的抑制
DOI：
10.1016/j.nbd.2014.09.011
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发表时间：
2015
影响因子：
6.1
通讯作者：
Raab-Graham, Kimberly F.
中科院分区：
文献类型：
--
作者：
Sosanya, Natasha M.;Brager, Darrin H.;Wolfe, Sarah;Niere, Farr;Raab-Graham, Kimberly F.
离子通道表达的变化与癫痫的病因有关。然而，导致离子通道长期异常表达的分子尚不清楚。雷帕霉素的机制/哺乳动物靶标（mTOR）是一种丝氨酸/苏氨酸蛋白激酶，其介导神经元中的活性依赖性蛋白质合成。mTOR在癫痫中过度活跃，表明过度的蛋白质合成可能有助于神经元病理学。相反，我们发现mTOR活性和microRNA miR-129- 5 p降低了颞叶癫痫（TLE）动物模型中电压门控钾通道Kv1.1的表达。当mTOR活性低时，Kv1.1表达高，行为癫痫发作的频率低。然而，随着行为癫痫发作活动的增加，mTOR活性增加，Kv1.1蛋白水平下降。在CA 1锥体神经元中，Kv1.1的减少降低了动作电位放电的阈值。有趣的是，用雷帕霉素阻断mTOR活性可以减少行为性癫痫发作，并暂时保持Kv1.1水平升高。随着时间的推移，所有动物的癫痫发作活动增加，Kv1.1蛋白减少，即使是用雷帕霉素治疗的动物。值得注意的是，Kv1.1 mRNA翻译负调节因子miR-129- 5 p的浓度在癫痫持续状态（SE）后21天增加，维持Kv1.1 mRNA翻译抑制。我们的研究结果表明，在红藻氨酸诱导的癫痫持续状态后，Kv1.1的抑制有两个阶段：（1）Kv1.1的初始mTOR依赖性抑制，随后是（2）Kv1.1的miR-129- 5 p持续减少。
Changes in ion channel expression are implicated in the etiology of epilepsy. However, the molecular leading to long-term aberrant expression of ion channels are not well understood. The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons. mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology. In contrast, we found that mTOR activity and the microRNA miR-129-5p reduce the expression of the voltage-gated potassium channel Kv1.1 in an animal model of temporal lobe epilepsy (TLE). When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low. However, as behavioral seizure activity rises, mTOR activity increases and Kv1.1 protein levels drop. In CA1 pyramidal neurons, the reduction in Kv1.1 lowers the threshold for action potential firing. Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated. Overtime, seizure activity increases and Kv1.1 protein decreases in all animals, even those treated with rapamycin. Notably, the concentration of miR-129-5p, the negative regulator of Kv1.1 mRNA translation, increases by 21 days post-status epilepticus (SE), sustaining Kv1.1 mRNA translational repression. Our results suggest that following kainic-acid induced status epilepticus there are two phases of Kv1.1 repression: (1) an initial mTOR-dependent repression of Kv1.1 that is followed by (2) a miR-129-5p persistent reduction of Kv1.1.
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DOI：
10.1016/0013-4694(72)90177-0
发表时间：
1972-01-01
期刊：
ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY
影响因子：
--
作者：
RACINE, RJ
通讯作者：
RACINE, RJ
癫痫持续状态在神经元死亡前会降低海马锥体细胞中谷氨酸受体 2 mRNA 和蛋白的表达。
DOI：
10.1073/pnas.97.7.3631
发表时间：
2000
影响因子：
11.1
作者：
Grooms,SY;Opitz,T;Bennett,MV;Zukin,RS
通讯作者：
Zukin,RS
影响因子：
3.5
作者：
Lee, Hane;Lin, Meng-chin A.;Nelson, Stanley F.
通讯作者：
Nelson, Stanley F.
影响因子：
1.3
作者：
Wong M
通讯作者：
Wong M
影响因子：
2.5
作者：
Narayanan, Rishikesh;Johnston, Daniel
通讯作者：
Johnston, Daniel