Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system.
Tissue-type plasminogen activator is a homeostatic regulator of synaptic function in the central nervous system.
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DOI：
10.4103/1673-5374.202924
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发表时间：
2017-03
影响因子：
6.1
通讯作者：
Yepes M
中科院分区：
文献类型：
--
作者：
Jeanneret V;Yepes M
膜去极化诱导大脑皮层神经元突触前终末释放丝氨酸蛋白酶组织型纤溶酶原激活物(TPA)。一旦进入突触间隙，这种tPA促进含谷氨酸的突触小泡的胞吐和随后的内吞回收，并调节突触后对突触前谷氨酸释放的反应。事实上，tPA对突触后密度(PSD)的组成具有双向影响，不需要纤溶酶的产生或突触前谷氨酸的释放，但会随着神经元活动的基线水平而变化。因此，在非活动神经元中，tPA诱导钙/钙调蛋白依赖性蛋白激酶IIα(pCaMKIIα)的磷酸化并在PSD中积聚，随后pCaMKIIα诱导含有GluR1的AMPA受体的磷酸化和突触募集。相反，在PSD中pCaMKIIα水平升高的活跃神经元中，tPA诱导pCaMKIIα和pGluR1去磷酸化，并随后将它们从PSD中移除。这些作用需要激活的突触N-甲基-D-天冬氨酸(NMDA)受体和细胞周期蛋白依赖性激酶5(CDK5)诱导的蛋白磷酸酶1(PP1)在T320处的磷酸化。这些数据表明，tPA是一种动态平衡调节剂，通过双向调节PSD中的pCaMKIIα/PP1开关，调节大脑皮层神经元对突触前谷氨酸释放的突触后反应。
Membrane depolarization induces the release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons. Once in the synaptic cleft this tPA promotes the exocytosis and subsequent endocytic retrieval of glutamate-containing synaptic vesicles, and regulates the postsynaptic response to the presynaptic release of glutamate. Indeed, tPA has a bidirectional effect on the composition of the postsynaptic density (PSD) that does not require plasmin generation or the presynaptic release of glutamate, but varies according to the baseline level of neuronal activity. Hence, in inactive neurons tPA induces phosphorylation and accumulation in the PSD of the Ca2+/calmodulin-dependent protein kinase IIα (pCaMKIIα), followed by pCaMKIIα-induced phosphorylation and synaptic recruitment of GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In contrast, in active neurons with increased levels of pCaMKIIα in the PSD tPA induces pCaMKIIα and pGluR1 dephosphorylation and their subsequent removal from the PSD. These effects require active synaptic N-methyl-D-aspartate (NMDA) receptors and cyclin-dependent kinase 5 (Cdk5)-induced phosphorylation of the protein phosphatase 1 (PP1) at T320. These data indicate that tPA is a homeostatic regulator of the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate via bidirectional regulation of the pCaMKIIα /PP1 switch in the PSD.