Endocytosis of GluN2B-containing NMDA receptors mediates NMDA-induced excitotoxicity.
Endocytosis of GluN2B-containing NMDA receptors mediates NMDA-induced excitotoxicity.
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含 GluN2B 的 NMDA 受体的内吞作用介导 NMDA 诱导的兴奋性毒性
DOI：
10.1177/1744806917701921
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发表时间：
2017-01
期刊：
影响因子：
3.3
通讯作者：
Qiu S
中科院分区：
文献类型：
--
作者：
Wu Y;Chen C;Yang Q;Jiao M;Qiu S
N-甲基-D-天冬氨酸(NMDA)受体过度激活参与了卒中后神经元的损伤。然而，NMDA受体介导的兴奋性毒性的机制仍不清楚。在这项研究中，我们证实了NMDARs的过度激活导致了PC12细胞和原代培养的皮质神经元的细胞凋亡，这主要是由含有GluN2B的NMDARs介导的，而不是含有GluN2A的NMDARs。此外，依赖于笼蛋白的内吞作用参与了NMDA诱导的兴奋性毒性。此外，我们发现在过量的NMDA处理过程中，含有GluN2B的NMDARs发生了内吞作用。特异性干扰GluN2B与AP-2复合体相互作用的多肽不仅可以阻断NMDA诱导的GluN2B的内吞作用，而且可以消除NMDA诱导的兴奋性毒性。这些结果表明，含GluN2B的NMDARs的胞内吞噬功能在NMDA诱导的PC12细胞和原代培养的皮层神经元的兴奋性毒性中起关键作用，从而为阻断NMDAR介导的兴奋性毒性提供了一个新的靶点。
N-methyl-D-aspartate (NMDA) receptor overactivation is involved in neuronal damage after stroke. However, the mechanism underlying NMDA receptor-mediated excitotoxicity remains unclear. In this study, we confirmed that excessive activation of NMDARs led to cell apoptosis in PC12 cells and in primary cultured cortical neurons, which was mediated predominantly by the GluN2B-containing, but not the GluN2A-containing NMDARs. In addition, Clathrin-dependent endocytosis participated in NMDA-induced excitotoxicity. Furthermore, we identified that GluN2B-containing NMDARs underwent endocytosis during excessive NMDA treatment. Peptides specifically disrupting the interaction between GluN2B and AP-2 complex not only blocked endocytosis of GluN2B induced by NMDA treatment but also abolished NMDA-induced excitotoxicity. These results demonstrate that Clathrin-dependent endocytosis of GluN2B-containing NMDARs is critical to NMDA-induced excitotoxicity in PC12 cells and in primary cultured cortical neurons, and therefore provide a novel target for blocking NMDAR-mediated excitotoxicity.