Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.
Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand.
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DOI：
10.1523/jneurosci.1207-08.2008
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发表时间：
2008-10-15
影响因子：
5.3
通讯作者：
Hardingham, Giles E.
中科院分区：
文献类型：
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作者：
Soriano, Francesc X.;Martel, Marc-Andre;Papadia, Sofia;Vaslin, Anne;Baxter, Paul;Rickman, Colin;Forder, Joan;Tymianski, Michael;Duncan, Rory;Aarts, Michelle;Clarke, Peter;Wyllie, David J. A.;Hardingham, Giles E.
关键词：
NMDA受体（NMDAR）介导缺血性脑损伤，其中NR 2亚基的C-末端与NMDAR信号传导复合物（NSC）内的PDZ结构域蛋白之间的相互作用是新兴的治疗靶点。然而，在缺乏许多NSC组分的非神经元环境中NMDAR的表达仍然可以诱导细胞死亡。此外，目前还不清楚靶向NSC是否会损害NMDAR依赖的促存活和可塑性信号传导。我们表明，NMDAR可以促进死亡信号独立的NR 2 PDZ配体，当在非神经元细胞缺乏PSD-95和nNOS，介导神经元NMDAR兴奋性毒性的关键PDZ蛋白表达。然而，在非神经元背景下，NMDAR仅通过JNK促进细胞死亡，而NMDAR依赖性皮质神经元死亡由JNK和p38两者促进。通过p38的NMDAR依赖性促死亡信号传导依赖于神经元背景，尽管由线粒体ROS产生触发的JNK的死亡信号传导不依赖于神经元背景。神经元中NMDAR依赖性p38激活由膜下Ca 2+触发，并被NOS抑制剂以及模拟NR 2B PDZ配体的肽（TAT-NR 2B 9 c）破坏。TAT-NR 2B 9 c减少兴奋毒性神经元死亡和p38介导的缺血性损伤，而不损害NMDAR依赖性可塑性模型，或CREB或Akt的促生存信号传导。TAT-NR 2B 9 c不抑制JNK活化，并与JNK抑制剂协同改善体外严重的兴奋毒性神经元损失和体内缺血性皮质损伤。因此，NMDAR激活的信号包括对PDZ蛋白相互作用具有不同要求的促死亡途径。这些信号适合于选择性抑制，同时保留突触可塑性和促存活信号。
NMDA receptors (NMDARs) mediate ischemic brain damage, for which interactions between the C-termini of NR2 subunits and PDZ domain proteins within the NMDAR signaling complex (NSC) are emerging therapeutic targets. However, expression of NMDARs in a non-neuronal context, lacking many NSC components, can still induce cell-death. Moreover, it is unclear if targeting the NSC will impair NMDAR-dependent pro-survival and plasticity signaling. We show that the NMDAR can promote death signaling independently of the NR2 PDZ ligand, when expressed in non-neuronal cells lacking PSD-95 and nNOS, key PDZ proteins which mediate neuronal NMDAR excitotoxicity. However, in a non-neuronal context the NMDAR promotes cell death solely via JNK, while NMDAR-dependent cortical neuronal death is promoted by both JNK and p38. NMDAR-dependent pro-death signaling via p38 relies on neuronal context, although death signaling by JNK, triggered by mitochondrial ROS production, does not. NMDAR-dependent p38 activation in neurons is triggered by submembranous Ca2+, and is disrupted by NOS inhibitors and also a peptide mimicking the NR2B PDZ ligand (TAT-NR2B9c). TAT-NR2B9c reduced excitotoxic neuronal death and p38-mediated ischemic damage, without impairing an NMDAR-dependent plasticity model, or pro-survival signaling to CREB or Akt. TAT-NR2B9c did not inhibit JNK activation, and synergized with JNK inhibitors to ameliorate severe excitotoxic neuronal loss in vitro and ischemic cortical damage in vivo. Thus, NMDAR-activated signals comprise pro-death pathways with differing requirements for PDZ protein interactions. These signals are amenable to selective inhibition, while sparing synaptic plasticity and pro-survival signaling.