The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death.
The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death.
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DOI：
10.1083/jcb.200407024
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发表时间：
2005-01-03
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影响因子：
--
通讯作者：
Courtney MJ
中科院分区：
文献类型：
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作者：
Cao J;Viholainen JI;Dart C;Warwick HK;Leyland ML;Courtney MJ
应激活化蛋白激酶p38和一氧化氮（NO）被认为是兴奋性毒性细胞死亡的下游效应物。虽然突触后密度蛋白PSD 95可以募集钙依赖性神经元NO合酶（nNOS）的口的钙渗透性NMDA受体，和PSD 95的耗竭抑制兴奋性毒性，选择性解偶联的nNOS从PSD 95可能是神经保护的可能性是未知的。兴奋性毒性应激产生的NO和p38激活之间的关系以及PSD 95-nNOS相互作用对p38激活的意义也尚不清楚。我们发现，NOS抑制剂减少谷氨酸诱导的p38激活和由此产生的神经元死亡，而NO供体具有与NO一致的作用，作为谷氨酸诱导的细胞死亡中p38的上游调节剂。使用靶向PSD 95-nNOS相互作用的诱饵构建物的实验表明，这种相互作用和随后的NO产生对于谷氨酸诱导的p38激活和随后的细胞死亡是至关重要的，并证明PSD 95-nNOS界面为设计具有增加的选择性的神经保护药物提供了真正的可能性。
The stress-activated protein kinase p38 and nitric oxide (NO) are proposed downstream effectors of excitotoxic cell death. Although the postsynaptic density protein PSD95 can recruit the calcium-dependent neuronal NO synthase (nNOS) to the mouth of the calcium-permeable NMDA receptor, and depletion of PSD95 inhibits excitotoxicity, the possibility that selective uncoupling of nNOS from PSD95 might be neuroprotective is unexplored. The relationship between excitotoxic stress–generated NO and activation of p38, and the significance of the PSD95–nNOS interaction to p38 activation also remain unclear. We find that NOS inhibitors reduce both glutamate-induced p38 activation and the resulting neuronal death, whereas NO donor has effects consistent with NO as an upstream regulator of p38 in glutamate-induced cell death. Experiments using a panel of decoy constructs targeting the PSD95–nNOS interaction suggest that this interaction and subsequent NO production are critical for glutamate-induced p38 activation and the ensuing cell death, and demonstrate that the PSD95–nNOS interface provides a genuine possibility for design of neuroprotective drugs with increased selectivity.