Long-term exposure to the atypical antipsychotic olanzapine differently up-regulates extracellular signal-regulated kinases 1 and 2 phosphorylation in subcellular compartments of rat prefrontal cortex
Long-term exposure to the atypical antipsychotic olanzapine differently up-regulates extracellular signal-regulated kinases 1 and 2 phosphorylation in subcellular compartments of rat prefrontal cortex
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DOI：
10.1124/mol.105.019828
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发表时间：
2006-04-01
影响因子：
3.6
通讯作者：
Riva, MA
中科院分区：
文献类型：
--
作者：
Fumagalli, F;Frasca, A;Riva, MA
抗精神病药是治疗精神分裂症的首选药物。除了阻断单胺受体外，这些分子还影响细胞内信号传导机制，导致长期突触改变。采用蛋白质印迹分析研究长期给药（14 天）典型抗精神病药氟哌啶醇和非典型奥氮平对细胞外信号相关激酶 (ERK) 1 和 2 (ERK1/2) 表达和磷酸化状态的影响，这些蛋白参与多种细胞内信号级联的调节。两种药物的单次注射均导致不同亚细胞区室中 ERK1/2 磷酸化的整体降低。相反，长期使用奥氮平（而非氟哌啶醇）治疗会以隔室特异性和时间依赖性方式增加前额皮质中的 ERK1/2 磷酸化。事实上，最后一次给药后 2 小时，ERK1/2 磷酸化在细胞核和细胞质部分中升高，而当动物在最后一次注射后 24 小时处死时，仅在膜部分中增强。这种效应可能是丝裂原激活蛋白激酶途径激活的结果，因为长期服用奥氮平也增加了细胞外信号调节激酶激酶1/2的磷酸化。我们的数据表明，长期暴露于奥氮平可动态调节不同亚细胞区室中的 ERK1/2 磷酸化，揭示了这种非典型药物的新作用机制，并指出了长期奥氮平给药后由这些激酶介导的信号事件的时间分离位置。
Antipsychotics are the drugs of choice for the treatment of schizophrenia. Besides blocking monoamine receptors, these molecules affect intracellular signaling mechanisms, resulting in long-term synaptic alterations. Western blot analysis was used to investigate the effect of long-term administration (14 days) with the typical antipsychotic haloperidol and the atypical olanzapine on the expression and phosphorylation state of extracellular signal-related kinases (ERKs) 1 and 2 (ERK1/2), proteins involved in the regulation of multiple intracellular signaling cascades. A single injection of both drugs produced an overall decrease in ERK1/2 phosphorylation in different subcellular compartments. Conversely, long-term treatment with olanzapine, but not haloperidol, increased ERK1/2 phosphorylation in the prefrontal cortex in a compartment-specific and time-dependent fashion. In fact, ERK1/2 phosphorylation was elevated in the nuclear and cytosolic fractions 2 h after the last drug administration, whereas it was enhanced only in the membrane fraction when the animals were killed 24 h after the last injection. This effect might be the result of an activation of the mitogen-activated protein kinase pathway, because the phosphorylation of extracellular signal-regulated kinase kinase 1/2 was also increased by long-term olanzapine administration. Our data demonstrate that long-term exposure to olanzapine dynamically regulates ERK1/2 phosphorylation in different subcellular compartments, revealing a novel mechanism of action for this atypical agent and pointing to temporally separated locations of signaling events mediated by these kinases after long-term olanzapine administration.