Metabotropic glutamate receptor 5 promotes proliferation of human neural stem/progenitor cells with activation of mitogen-activated protein kinases signaling pathway in vitro
Metabotropic glutamate receptor 5 promotes proliferation of human neural stem/progenitor cells with activation of mitogen-activated protein kinases signaling pathway in vitro
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DOI：
10.1016/j.neuroscience.2011.06.044
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发表时间：
2011-09
期刊：
影响因子：
3.3
通讯作者：
Lingyu Zhao;Q. Jiao;Peng-bo Yang;Xi Chen;Jianshui Zhang;B. Zhao;Peng Zheng;Y. Liu
中科院分区：
文献类型：
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作者：
Lingyu Zhao;Q. Jiao;Peng-bo Yang;Xi Chen;Jianshui Zhang;B. Zhao;Peng Zheng;Y. Liu
代谢型谷氨酸受体（Metabotropic glutamate receptor，mGluRs）在脑内调控神经发生，但其机制尚不清楚。在这项研究中，我们研究了mGluR 5对人胚胎神经干/祖细胞（NPC）的增殖，细胞周期蛋白D1的表达和丝裂原活化蛋白激酶（MAPK）信号通路的激活的影响。结果显示，mGluR 5激动剂（S）-3，5-二羟基苯甘氨酸（DHPG）通过增加细胞活性、神经球直径和细胞分裂促进NPC增殖，而mGluR 5 siRNA和拮抗剂6-甲基-2-（苯乙炔基）吡啶盐酸盐（MPEP）则抑制NPC增殖。细胞周期蛋白D1的mRNA和蛋白表达随DHPG处理而增加，siRNA或MPEP处理后下降。细胞外信号调节蛋白激酶（ERK）和c-Jun N-末端蛋白激酶（JNK）信号通路的激活也参与了NPC的增殖。DHPG处理后p-ERK 1/2和p-JNK 2水平升高，p-p38水平降低; siRNA或MPEP处理后p-ERK 1/2和p-JNK 2水平降低，p-p38水平升高。我们的研究结果表明，mGluR 5促进人胚胎皮层NPC的增殖和增加细胞周期蛋白D1的表达与MAPK信号通路的磷酸化的变化，在体外，提示一个新的药理学研究治疗缺血性脑损伤和神经退行性疾病的机制。
Metabotropic glutamate receptors (mGluRs) regulate neurogenesis in brain, but the mechanisms remain unknown. In this study, we investigated the effect of mGluR5 on the proliferation of human embryonic neural stem/progenitor cells (NPCs), the expression of cyclin D1 and the activation of signaling pathways of mitogen-activated protein kinases (MAPKs). Results showed that mGluR5 agonist (S)-3,5-dihydroxyphenylglycine hydrate (DHPG) increased the proliferation of NPCs by increasing cell activity, diameter of neurospheres and cell division, while mGluR5 siRNA and antagonist 6-methyl-2-(phenylethynyl) pyridine hydrochloride (MPEP) decreased the NPC proliferation. The mRNA and protein expressions of cyclin D1 increased with DHPG treatment and decreased after siRNA or MPEP treatment. It was also found that activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal protein kinase (JNK) signaling pathways were involved in the proliferation of NPCs. After DHPG treatment, p-ERK1/2 and p-JNK2 levels increased, and meanwhile p-p38 level decreased; but p-ERK1/2 and p-JNK2 levels decreased after siRNA or MPEP treatment, and p-p38 level increased. Our findings demonstrated that mGluR5 promoted the proliferation of human embryonic cortical NPCs and increased cyclin D1 expression with the changes in phosphorylation of MAPKs signaling pathways in vitro, suggesting a novel mechanism for pharmacological study of treatment for ischemic brain injury and neurodegenerative disorders.