Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons.
Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons.
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DOI：
10.1016/j.neuroscience.2016.01.046
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发表时间：
2016-04-05
期刊：
影响因子：
3.3
通讯作者：
Cheng L
中科院分区：
文献类型：
--
作者：
Yepes M;Wu F;Torre E;Cuellar-Giraldo D;Jia D;Cheng L
丝氨酸蛋白酶组织型纤溶酶原激活物（tPA）在大脑皮层神经元突触前末梢的释放在突触可塑性的发育、对代谢应激的适应和神经元存活中起着重要作用。我们早期的研究表明，通过诱导细胞骨架蛋白β II-血影蛋白和电压门控钙通道向活动区（AZ）的募集，tPA促进突触囊泡（SV）向突触释放位点的Ca 2+依赖性易位，在突触释放位点，SV将其神经递质负荷释放到突触间隙中。在这里，我们使用了在体内和体外实验相结合，以调查是否这种影响会导致突触前末梢的SV耗尽。我们的数据表明，tPA通过一种不需要纤溶酶原转化为纤溶酶的机制促进SV内吞。相反，我们表明，tPA诱导钙调神经磷酸酶（CaN）介导的发动蛋白I去磷酸化，其次是发动蛋白I诱导的肌动蛋白结合蛋白profilin II的突触前膜的招聘，和profilin II诱导的F-肌动蛋白的形成。我们报告说，这tPA诱导的事件序列导致协会的新形成的SV与F-肌动蛋白簇的内吞区。总之，这里提供的数据表明，神经递质tPA的胞吐释放后激活的机制，使SV从突触前膜和胞吞收回，以补充池的囊泡可用于一个新的胞吐循环。总之，这些结果表明，在大脑皮层神经元tPA起着核心作用耦合SV胞吐和胞吞。
The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone (AZ), tPA promotes Ca2+-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. Our data indicate that tPA promotes SVs endocytosis via a mechanism that does not require the conversion of plasminogen into plasmin. Instead, we show that tPA induces calcineurin (CaN) - mediated dynamin I dephosphorylation, which is followed by dynamin I-induced recruitment of the actin binding protein profilin II to the presynaptic membrane, and profilin II-induced F-actin formation. We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis.