Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via regulating group I metabotropic glutamate receptors.
Postsynaptic scaffold protein Homer 1a protects against traumatic brain injury via regulating group I metabotropic glutamate receptors.
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突触后支架蛋白 Homer 1a 通过调节 I 类代谢型谷氨酸受体来预防创伤性脑损伤
DOI：
10.1038/cddis.2014.116
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发表时间：
2014-04-10
影响因子：
9
通讯作者：
Fei Z
中科院分区：
文献类型：
--
作者：
Luo P;Chen T;Zhao Y;Zhang L;Yang Y;Liu W;Li S;Rao W;Dai S;Yang J;Fei Z
外伤性脑损伤（TBI）产生过量的谷氨酸，通过激活谷氨酸受体导致兴奋性毒性。突触后密度支架蛋白在谷氨酸受体到其下游介质的信号转导中起着至关重要的作用。因此，研究支架蛋白调控兴奋性毒性的机制可以发现新的TBI治疗方法。在这里，我们证明了突触后支架蛋白Homer 1a在体外和体内对TBI具有神经保护作用，并且这种神经保护作用与其对I组代谢性谷氨酸受体（mGluRs）的作用有关。通过进一步研究，我们发现Homer 1a主要影响脑外伤后mGluR1激活引起的神经元损伤，在mGluR5活性恢复后也会影响其功能。Homer 1a破坏mGluR-ERK信号的能力有助于其在创伤损伤后调节mGluR1和mGluR5的功能。细胞内ca2 +和PKC是Homer 1a介导mGluR-ERK信号传导的两个重要因子。这些结果确定Homer 1a是一种新的内源性神经保护剂。
Traumatic brain injury (TBI) produces excessive glutamate, leading to excitotoxicity via the activation of glutamate receptors. Postsynaptic density scaffold proteins have crucial roles in mediating signal transduction from glutamate receptors to their downstream mediators. Therefore, studies on the mechanisms underlying regulation of excitotoxicity by scaffold proteins can uncover new treatments for TBI. Here, we demonstrated that the postsynaptic scaffold protein Homer 1a was neuroprotective against TBI in vitro and in vivo, and this neuroprotection was associated with its effects on group I metabotropic glutamate receptors (mGluRs). Upon further study, we found that Homer 1a mainly affected neuronal injury induced by mGluR1 activation after TBI and also influenced mGluR5 function when its activity was restored. The ability of Homer 1a to disrupt mGluR-ERK signaling contributed to its ability to regulate the functions of mGluR1 and mGluR5 after traumatic injury. Intracellular Ca 2+ and PKC were two important factors involved in the mediation of mGluR-ERK signaling by Homer 1a. These results define Homer 1a as a novel endogenous neuroprotective agent against TBI.