Bhat R V, Engber T M, Finn J P, Koury E J, Contreras P C, Miller M S, Dionne C A, Walton K M
Department of Pharmacology, Cephalon, West Chester, Pennsylvania, USA.
J Neurochem. 1998 Feb;70(2):558-71. doi: 10.1046/j.1471-4159.1998.70020558.x.
In vitro studies indicate that p42/p44MAPK phosphorylate both nuclear and cytoplasmic proteins. However, the functional targets of p42/p44MAPK activation in vivo remain unclear. To address this question, we localized activated p42/p44MAPK in hippocampus and cortex and determined their signaling effects after electroconvulsive shock treatment (ECT) in rats. Phosphorylated p42/p44MAPK content increased in the cytoplasm of hippocampal neurons in response to ECT. Consistent with this cytoplasmic localization, inhibition of ECT-induced p42/p44MAPK activation by the extracellular signal-regulated kinase kinase inhibitor PD098059 blocked phosphorylation of the cytoplasmic protein microtubule-associated protein 2c (MAP2c), but failed to inhibit the induction of the nuclear protein c-Fos in response to ECT. In contrast to hippocampal neurons, cortical neurons exhibited an increase in amount of phosphorylated p42/p44MAPK in both the nucleus and cytoplasm after ECT. Accordingly, PD098059 blocked the induction of Fos-like immunoreactivity in the nuclei of cortical neurons as well as MAP2c phosphorylation in the cytoplasm. Our data indicate that both nuclear and cytoplasmic substrates can be activated by p42/p44MAPK in vivo. However, the functional targets of p42/p44MAPK signaling depend on the precise location of p42/p44MAPK within different subcellular compartments of brain regions. These results indicate unique functional pathways of p42/p44MAPK-mediated signal transduction within different brain regions in vivo.
体外研究表明，p42/p44丝裂原活化蛋白激酶（MAPK）可使细胞核和细胞质中的蛋白质磷酸化。然而，p42/p44MAPK在体内的功能靶点仍不清楚。为了解决这个问题，我们在海马体和皮层中定位了活化的p42/p44MAPK，并确定了大鼠经电惊厥休克治疗（ECT）后它们的信号转导效应。ECT刺激后，海马神经元细胞质中磷酸化的p42/p44MAPK含量增加。与这种细胞质定位一致，细胞外信号调节激酶激酶抑制剂PD098059抑制ECT诱导的p42/p44MAPK活化，可阻断细胞质蛋白微管相关蛋白2c（MAP2c）的磷酸化，但未能抑制ECT刺激后核蛋白c-Fos的诱导。与海马神经元不同，ECT刺激后，皮层神经元细胞核和细胞质中磷酸化的p42/p44MAPK含量均增加。因此，PD098059可阻断皮层神经元细胞核中Fos样免疫反应性的诱导以及细胞质中MAP2c的磷酸化。我们的数据表明，在体内p42/p44MAPK可激活细胞核和细胞质中的底物。然而，p42/p44MAPK信号转导的功能靶点取决于p42/p44MAPK在脑区不同亚细胞区室中的精确位置。这些结果表明，在体内不同脑区中p42/p44MAPK介导的信号转导具有独特的功能途径。
