Nuclear translocation of nuclear transcription factor-κB by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons
Nuclear translocation of nuclear transcription factor-κB by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors leads to transcription of p53 and cell death in dopaminergic neurons
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DOI：
10.1124/mol.63.4.784
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发表时间：
2003-04-01
影响因子：
3.6
通讯作者：
Dugan, LL
中科院分区：
文献类型：
--
作者：
de Erausquin, GA;Hyrc, K;Dugan, LL
在大鼠胚胎培养的多巴胺能神经元中，我们描述了核转录因子kappaB(NFkappaB)介导的兴奋毒性导致细胞死亡的一种新的分子机制。用alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸(AMPA)处理中脑培养的多巴胺能神经元发生了许多选择性的变化，包括Fura-2监测的细胞内钙离子的持续升高，以及线粒体内二氢罗丹明123氧化的显著增加，这可能与线粒体通透性的一过性增加，细胞色素c的释放，NFkappaB的核移位，以及癌基因p53的转录激活有关。这些步骤中的任何一个都被特定的拮抗剂阻断，阻止了轴突的修剪和程序性细胞死亡。相反，caspase拮抗剂并不能阻止细胞死亡，一氧化氮合酶抑制剂只能部分阻止细胞死亡。这一信号转导途径可能。是帕金森病持续神经元死亡的一种贡献机制。
We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor kappaB (NFkappaB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca2+ monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably associated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NFkappaB, and transcriptional activation of the oncogene p53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might. be a contributing mechanism in ongoing neuronal death in Parkinson disease.