Institut National de Santé et de Recherche Médicale, U919, Serine Proteases and Pathophysiology of Neurovascular Unit, Université de Caen, Groupement d'Internet Public Cyceron, 14073 Caen Cedex, France.
J Neurosci. 2012 Apr 11;32(15):5186-99. doi: 10.1523/JNEUROSCI.5296-11.2012.
Tissue-type plasminogen activator (tPA) regulates physiological processes in the brain, such as learning and memory, and plays a critical role in neuronal survival and neuroinflammation in pathological conditions. Here we demonstrate, by combining mouse in vitro and in vivo data, that tPA is an important element of the cross talk between neurons and astrocytes. The data show that tPA released by neurons is constitutively endocytosed by astrocytes via the low-density lipoprotein-related protein receptor, and is then exocytosed in a regulated manner. The exocytotic recycling of tPA by astrocytes is inhibited in the presence of extracellular glutamate. Kainate receptors of astrocytes act as sensors of extracellular glutamate and, via a signaling pathway involving protein kinase C, modulate the exocytosis of tPA. Further, by thus capturing extracellular tPA, astrocytes serve to reduce NMDA-mediated responses potentiated by tPA. Overall, this work provides the first demonstration that the neuromodulator, tPA, may also be considered as a gliotransmitter.
组织型纤溶酶原激活物（tPA）调节大脑中的生理过程，如学习和记忆，并在病理条件下对神经元存活和神经炎症发挥关键作用。在这里，我们通过结合小鼠体外和体内数据证明，tPA 是神经元和星形胶质细胞之间串扰的重要组成部分。数据表明，神经元释放的 tPA 通过低密度脂蛋白相关蛋白受体被星形胶质细胞持续内吞，并以受调控的方式外排。在存在细胞外谷氨酸的情况下，星形胶质细胞中 tPA 的外排性再循环被抑制。星形胶质细胞的 kainate 受体作为细胞外谷氨酸的传感器，并通过涉及蛋白激酶 C 的信号通路调节 tPA 的外排。此外，星形胶质细胞通过捕获细胞外的 tPA，有助于降低 tPA 增强的 NMDA 介导的反应。总的来说，这项工作首次证明神经调节剂 tPA 也可被视为一种神经递质。
