Involvement of the delayed rectifier outward potassium channel Kv2.1 in methamphetamine-induced neuronal apoptosis via the p38 mitogen-activated protein kinase signaling pathway
Involvement of the delayed rectifier outward potassium channel Kv2.1 in methamphetamine-induced neuronal apoptosis via the p38 mitogen-activated protein kinase signaling pathway
复制标题
延迟整流外向钾通道 Kv2.1 通过 p38 丝裂原激活蛋白激酶信号通路参与甲基苯丙胺诱导的神经元凋亡
DOI：
10.1002/jat.3576
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发表时间：
2018
影响因子：
3.3
通讯作者：
Xiao Hang
中科院分区：
文献类型：
--
作者：
Zhu Jingying;Zang Songsong;Chen Xufeng;Jiang Lei;Gu Aihua;Cheng Jie;Zhang Li;Wang Jun;Xiao Hang
甲基苯丙胺是一种具有高度滥用潜力和严重神经毒性的非法精神兴奋剂。最近的研究表明，甲基苯丙胺引起的学习和记忆功能障碍可能部分揭示了神经元通道病的机制。Kv2.1是神经元的初级延迟整流钾通道，负责介导凋亡电流激增。然而，Kv2.1是否参与甲基安非他明介导的神经损伤尚不清楚。在本研究中，用甲基甲氧胺处理原代培养的海马神经元表明，甲基甲氧胺诱导Kv2.1蛋白表达呈时间和剂量依赖性增加，同时伴有cleaved - caspase 3升高和bcl - 2/bax比值下降。抑制剂GxTx - 1E阻断Kv2.1或敲低Kv2.1可明显消除甲基安非他明介导的促凋亡作用，表明Kv2.1在甲基安非他明介导的神经损伤中具有特殊作用。此外，p38丝裂原活化蛋白激酶（MAPK）信号被证明参与甲基甲氧基介导的Kv2.1上调和随后的促凋亡效应，因为使用p38 MAPK抑制剂可以显著减弱甲基甲氧基介导的Kv2.1上调和细胞凋亡。值得注意的是，sigma‐1受体激动剂PRE‐084可以明显减弱甲基甲氧胺诱导的Kv2.1表达上调、神经细胞凋亡和p38 MAPK激活。综上所述，这些结果揭示了冰毒诱导的神经死亡的新机制，对冰毒使用者的治疗干预具有重要意义。
Methamphetamine (Meth) is an illicit psychostimulant with high abuse potential and severe neurotoxicity. Recent studies have shown that dysfunctions in learning and memory induced by Meth may partially reveal the mechanisms of neuronal channelopathies. Kv2.1, the primary delayed rectifying potassium channel in neurons, is responsible for mediating apoptotic current surge. However, whether Kv2.1 is involved in Meth‐mediated neural injury remains unknown. In the present study, the treatment of primary cultured hippocampal neurons with Meth indicated that Meth induced a time‐ and dose‐dependent augmentation of Kv2.1 protein expression, accompanied by elevated cleaved‐caspase 3 and declined bcl‐2/bax ratio. The blockage of Kv2.1 with the inhibitor GxTx‐1E or the knockdown of the channel noticeably abrogated the pro‐apoptotic effects mediated by Meth, demonstrating the specific roles of Kv2.1 in Meth‐mediated neural damage. Additionally, the p38 mitogen‐activated protein kinase (MAPK) signaling was demonstrated to be involved in Meth‐mediated Kv2.1 upregulation and in the subsequent pro‐apoptotic effects, as treatment with a p38 MAPK inhibitor significantly attenuated Meth‐mediated Kv2.1 upregulation and cell apoptosis. Of note, PRE‐084, a sigma‐1 receptor agonist, obviously attenuated Meth‐induced upregulation of Kv2.1 expression, neural apoptosis and p38 MAPK activation. Taken together, these results reveal a novel mechanism involved in Meth‐induced neural death with implications for therapeutic interventions for Meth users.