Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole.
Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole.
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DOI：
10.1038/tp.2012.97
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发表时间：
2012-10-16
影响因子：
6.8
通讯作者：
Hashimoto K
中科院分区：
文献类型：
--
作者：
Ishima T;Iyo M;Hashimoto K
阿立哌唑是一种非典型的抗精神病药物，被批准用于治疗精神分裂症、双相情感障碍、严重抑郁障碍和自闭症等精神障碍。该药对多巴胺D2受体和5-羟色胺(5-HT)5-HT1a受体有部分激活性，对5-HT2a受体有拮抗作用。然而，确切的机械途径仍不清楚。在这项研究中，我们研究了阿立哌唑对轴突生长的影响。阿立哌唑显著增强神经生长因子(NGF)诱导的PC12细胞突起生长，并呈浓度依赖关系。5-HT1a受体拮抗剂Way-100635，而不是多巴胺D2受体拮抗剂舒必利，阻断了阿立哌唑的作用，尽管只是部分阻断。肌醇1，4，5-三磷酸(IP3)受体的特异性抑制剂和细胞内钙离子的螯合剂BAPTA-AM可阻断阿立哌唑的作用。此外，几种常见信号通路的特异性抑制剂(磷脂酶C-γ、磷脂酰肌醇-3激酶、哺乳动物雷帕霉素靶标、p38MAPK、c-jun氨基末端激酶、AKT、RAS、Raf、ERK、MAPK)也可阻断阿立哌唑的作用。利用蛋白质组学分析，我们发现阿立哌唑显著增加培养细胞中热休克蛋白Hsp90α的水平。Hsp90RNA干扰可显著减弱阿立哌唑对神经生长因子诱导的轴突生长的影响，但不能通过αα的阴性对照。这些结果表明，5-HT1a受体激活和通过IP3受体的钙信号通路及其下游的细胞信号通路在促进阿立哌唑诱导的神经突起生长中发挥作用。此外，阿立哌唑诱导的热休克蛋白90α蛋白表达增加可能是该药治疗机制的一部分。
Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D2 receptors and 5-hydroxytryptamine (5-HT) 5-HT1A receptors, and antagonistic activity at 5-HT2A receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT1A receptor antagonist WAY-100635, but not the dopamine D2 receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors and BAPTA-AM, a chelator of intracellular Ca2+, blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT1A receptor activation and Ca2+ signaling via IP3 receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug.
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影响因子：
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作者：
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通讯作者：
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DOI：
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