Li B S, Ma W, Zhang L, Barker J L, Stenger D A, Pant H C
Laboratory of Neurochemistry, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosci. 2001 Mar 1;21(5):1569-79. doi: 10.1523/JNEUROSCI.21-05-01569.2001.
Muscarinic acetylcholine receptor (mAChR), a member of the G-protein-coupled receptors (GPCRs) gene superfamily, has been shown to mediate the effects of acetylcholine on differentiation and proliferation in the CNS. However, the mechanism or mechanisms whereby mAChRs regulate cell proliferation remain poorly understood. Here we show that in vitro bFGF-expanded neural progenitor cells dissociated from rat cortical neuroepithelium express muscarinic acetylcholine receptor subtype mRNAs. We demonstrate that stimulation of these mAChRs with carbachol, a muscarinic agonist, activated extracellular-regulated kinases (Erk1/2) and phosphatidylinositol-3 kinase (PI-3K). This, in turn, stimulated DNA synthesis in neural progenitor cells. MEK inhibitor PD98059 and PI-3K inhibitors wortmannin and LY294002 inhibited a carbachol-induced increase in DNA synthesis. These findings indicate that the activation of both PI-3 kinase and MEK signaling pathways via muscarinic receptors is involved in stimulating DNA synthesis in the neural progenitor cells during early neurogenesis.
毒蕈碱型乙酰胆碱受体（mAChR）是G蛋白偶联受体（GPCRs）基因超家族的成员，已被证明可介导乙酰胆碱对中枢神经系统中细胞分化和增殖的影响。然而，mAChRs调节细胞增殖的具体机制仍知之甚少。在此我们表明，从大鼠皮质神经上皮解离的体外经碱性成纤维细胞生长因子（bFGF）扩增的神经祖细胞表达毒蕈碱型乙酰胆碱受体亚型mRNA。我们证明，用毒蕈碱激动剂卡巴胆碱刺激这些mAChRs，可激活细胞外调节激酶（Erk1/2）和磷脂酰肌醇-3激酶（PI-3K）。这进而刺激神经祖细胞中的DNA合成。MEK抑制剂PD98059以及PI-3K抑制剂渥曼青霉素和LY294002可抑制卡巴胆碱诱导的DNA合成增加。这些发现表明，在神经发生早期，通过毒蕈碱受体激活PI-3激酶和MEK信号通路均参与刺激神经祖细胞中的DNA合成。
