INSERM U, Cyceron, University of Caen Basse-Normandie, Caen, France.
Cell Death Differ. 2010 May;17(5):860-71. doi: 10.1038/cdd.2009.172. Epub 2009 Nov 13.
Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S(), 3R())-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDAR-dependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.
虽然其作用的分子基础仍存在争议，但组织型纤溶酶原激活物（tPA）是一种矛盾的脑蛋白酶，因为它有利于某些学习/记忆过程，但会增加兴奋性毒性神经元死亡。在这里，我们表明，在培养的皮质神经元中，tPA 选择性地促进包含 NR2D 的 N-甲基-D-天冬氨酸受体（NMDAR）依赖性激活。我们表明，tPA 通过 NMDAR 介导的信号转导和神经毒性可通过应用 NR2D 拮抗剂（菲并衍生物（2S（），3R（））-1-（菲并-2-羰基）哌嗪-2,3-二羧酸，PPDA）或敲低神经元 NR2D 表达来阻断。与皮质神经元形成鲜明对比的是，海马神经元在体外和体内均不表现出 NR2D，因此对 tPA 促进的 NMDAR 介导的神经毒性具有抗性。此外，我们已经表明，突触 NMDAR 的激活可以防止进一步的 tPA 依赖性 NMDAR 介导的神经毒性和对 PPDA 的敏感性。这项研究表明，先前描述的 tPA 的促神经毒性作用是通过包含 NR2D 的 NMDAR 依赖性细胞外信号调节激酶激活介导的，这种有害作用可通过突触前激活来预防。
