Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM
Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM
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DOI：
10.1002/glia.20464
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发表时间：
2007-02-01
期刊：
影响因子：
6.2
通讯作者：
Simi, Anastasia
中科院分区：
文献类型：
--
作者：
Edling, Ylva;Ingelman-Sundberg, Magnus;Simi, Anastasia
C-fos在脑内的激活与神经元活动与基因表达的偶联有关，也与癫痫发作或兴奋性毒性诱导的细胞死亡等病理条件有关。谷氨酸通过NMDA受体下游的ERK和/或CaM-KIV激酶途径激活CREB的钙依赖性磷酸化，从而激活神经元中的c-fos。然而，在神经胶质细胞中，谷氨酸对c-fos的激活知之甚少。由于神经胶质细胞主动调节神经元兴奋性和大脑对损伤的反应，我们研究了谷氨酸激活大鼠皮质神经胶质细胞c-fos的机制。谷氨酸以钙依赖的方式诱导c-fos基因的表达，钙离子螯合剂BA-PTA-AM证实了这一点。谷氨酸诱导的c-fos基因表达对ERK、p38(MAPK)或CaMK信号通路的抑制剂不敏感，提示神经胶质细胞c-fos的激活有不同的机制。Thapsigargin可阻断谷氨酸对c-fos基因表达的影响，提示内质网钙动员。此外，谷氨酸诱导c-fos基因表达对mGluR5拮抗剂MPEP敏感，而对NMDA-R拮抗剂MK-801不敏感。在荧光素酶报告的分析中，通过结合钙结合的转录抑制物DREAM而积极抑制c-fos的Dre被谷氨酸激活，而SRE和Cre不被激活。最后，谷氨酸导致星形胶质细胞中DREAM的核输出，将DREAM的突变变体与DNA结构性结合后，星形胶质细胞抑制了谷氨酸诱导的c-Fos表达。这些发现与神经元中所描述的机制形成了鲜明的对比，并表明了一种由谷氨酸激活的神经胶质细胞中的新途径，该途径利用mGluR5、ER钙和c-fos在Dre处的去抑制。(C)2006年Wiley-Liss，Inc.
Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaM-KIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BA-PTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38(MAPK), or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE. (c) 2006 Wiley-Liss, Inc.