Proteomics and Mass Spectrometry Core Facility, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a str, 30-387, Krakow, Poland.
Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics Polish Academy of Sciences, Pawinskiego 5a, Warsaw, Poland.
Neurochem Res. 2021 Aug;46(8):2097-2111. doi: 10.1007/s11064-021-03348-4. Epub 2021 May 23.
Although antipsychotics are routinely used in the treatment of schizophrenia for the last decades, their precise mechanism of action is still unclear. In this study, we investigated changes in the PC12 cells' proteome under the influence of clozapine, risperidone, and haloperidol to identify protein pathways regulated by antipsychotics. Analysis of the protein profiles in two time points: after 12 and 24 h of incubation with drugs revealed significant alterations in 510 proteins. Further canonical pathway analysis revealed an inhibition of ciliary trophic factor signaling after treatment with haloperidol and showed a decrease in acute phase response signaling in the risperidone group. Interestingly, all tested drugs have caused changes in PC12 proteome which correspond to inhibition of cytokines: tumor necrosis factor (TNF) and transforming growth factor beta 1 (TGF-β1). We also found that the 12-h incubation with clozapine caused up-regulation of protein kinase A signaling and translation machinery. After 24 h of treatment with clozapine, the inhibition of the actin cytoskeleton signaling and Rho proteins signaling was revealed. The obtained results suggest that the mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) play a central role in the signal transduction of clozapine.
尽管抗精神病药在过去几十年中被常规用于治疗精神分裂症，但它们的确切作用机制仍不清楚。在这项研究中，我们研究了氯氮平、利培酮和氟哌啶醇对 PC12 细胞蛋白质组的影响，以确定抗精神病药调节的蛋白质途径。在药物孵育 12 和 24 小时后的两个时间点分析蛋白质图谱，揭示了 510 种蛋白质的显著变化。进一步的经典途径分析显示，氟哌啶醇治疗后抑制纤毛营养因子信号，利培酮组急性相反应信号下降。有趣的是，所有测试的药物都导致 PC12 蛋白质组发生变化，这与细胞因子（肿瘤坏死因子 (TNF) 和转化生长因子β 1 (TGF-β1)）的抑制有关。我们还发现，氯氮平孵育 12 小时会导致蛋白激酶 A 信号和翻译机制的上调。氯氮平治疗 24 小时后，揭示了肌动蛋白细胞骨架信号和 Rho 蛋白信号的抑制。研究结果表明，雷帕霉素靶蛋白复合物 1 (mTORC1) 和 2 (mTORC2) 在氯氮平的信号转导中起核心作用。
