Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury
Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury
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Preso 通过调节创伤性脑损伤后一氧化氮和钙反应来调节 NMDA 受体介导的兴奋性毒性
DOI：
10.1038/s41419-019-1731-x
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发表时间：
2019
影响因子：
9
通讯作者：
Lu Hongbing
中科院分区：
文献类型：
--
作者：
Luo Peng;Li Xin;Wu Xiuquan;Dai Shuhui;Yang Yuefan;Xu Haoxiang;Jing Da;Rao Wei;Xu Hongyu;Gao Xiangyu;Fei Zhou;Lu Hongbing
创伤性脑损伤（TBI）已成为世界范围内的主要健康问题，TBI的不良结局增加了对治疗改进的需求。TBI后的继发性损伤，包括兴奋性毒性，导致突触功能障碍，并提供了潜在的干预目标。突触后支架蛋白参与神经元损伤后兴奋性毒性的调节，在调节突触功能中起着至关重要的作用。因此，探索突触后支架蛋白在TBI中的作用可能会发现新的治疗方法。在这项研究中，我们证明了突触后支架蛋白Preso的表达下调，在体外和体内TBI后保护神经元损伤，这些作用与抑制N-甲基-D-天冬氨酸受体（NMDAR）功能有关。进一步的研究表明，Preso促进NMDAR信号传导到一氧化氮（NO）和钙（Ca 2+）反应。首先，复合物构成的NMDAR，突触后密度-95（PSD-95），和神经元型一氧化氮合酶（nNOS）被证明是参与Preso调节NO反应。解偶联Preso和PSD-95之间的连接减弱了该复合物的稳定性，并抑制了Preso对NO反应的调节作用。此外，细胞周期蛋白依赖性激酶5（CDK 5）对NMDAR的磷酸化被证明负责Preso介导的Ca 2+反应，这依赖于Preso和CDK 5之间的相互作用。这些结果表明，Preso与NMDAR信号传导的关联可以作为针对TBI的神经保护的靶标。
Traumatic brain injury (TBI) has become a major health concern worldwide, and the poor outcome of TBI increases the need for therapeutic improvement. Secondary injuries following TBI, including excitotoxicity, lead to synaptic dysfunction and provide potential targets for intervention. Postsynaptic scaffold proteins, which are involved in the regulation of excitotoxicity after neuronal injury, play a crucial role in modulating synaptic function. Therefore, exploring the role of postsynaptic scaffold proteins in TBI might uncover new treatments. In this study, we demonstrated that downregulated expression of the postsynaptic scaffold protein Preso protects against neuronal injury after TBI in vitro and in vivo, and these effects are related to the inhibition of N-methyl-D-aspartate receptor (NMDAR) function. Further study showed that Preso facilitates signaling from NMDAR to nitric oxide (NO) and calcium (Ca2+) responses. First, the complex constituting NMDAR, postsynaptic density-95 (PSD-95), and neuronal nitric oxide synthase (nNOS) was shown to be involved in the Preso regulation of the NO response. Uncoupling the linkage between Preso and PSD-95 attenuated the stability of this complex and suppressed the regulatory effect of Preso on the NO response. In addition, phosphorylation of NMDAR by cyclin-dependent kinase 5 (CDK5) was shown to be responsible for the Preso-mediated Ca2+response, which was dependent on the interaction between Preso and CDK5. These results suggested that the association of Preso with NMDAR signaling can serve as a target for neuroprotection against TBI.