Scaffolding protein Homer1a protects against NMDA-induced neuronal injury.
Scaffolding protein Homer1a protects against NMDA-induced neuronal injury.
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支架蛋白 Homer1a 可防止 NMDA 诱导的神经元损伤
DOI：
10.1038/cddis.2015.216
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发表时间：
2015-08-06
影响因子：
9
通讯作者：
Fei Z
中科院分区：
文献类型：
--
作者：
Wang Y;Rao W;Zhang C;Zhang C;Liu MD;Han F;Yao LB;Han H;Luo P;Su N;Fei Z
过量的N-甲基-D-天冬氨酸受体（NMDAR）活化和由此产生的神经元型一氧化氮合酶（nNOS）活化引起神经元损伤。Homer 1b/c促进NMDAR-PSD 95-nNOS复合物相互作用，Homer 1a是Homer 1b/c的负竞争者。我们报告说，Homer 1a的上调和保护对NMDA诱导的神经元损伤在体外和体内。Homer 1a的神经保护作用与NMDA诱导的Ca 2+内流、氧化应激及下游信号通路激活有关。此外，我们发现Homer 1a在功能上调节神经元中的NMDAR通道特性，但不调节HEK 293细胞中的重组NR 1/NR 2B受体。此外，我们发现Homer 1a分离了NR 2B，PSD 95和nNOS之间的物理联系，减少了NMDAR的膜分布。与野生型小鼠（WT，Homer 1a +/+）中NMDA诱导的神经元损伤相比，Homer 1a纯合子敲除小鼠（KO，Homer 1a −/−）中NMDA诱导的神经元损伤更严重。此外，Homer 1a −/−小鼠皮质中Homer 1a过表达减轻了NMDA诱导的神经元损伤。这些发现表明Homer 1a可能是一种关键的神经保护性内源性分子，通过分解NR 2B-PSD 95-nNOS复合物和减少NMDAR的膜分布来保护NMDA诱导的神经元损伤。
Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca 2+ influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a−/−) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a+/+). Additionally, Homer1a overexpression in the cortex of Homer1a−/− mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs.