Normandie Univ, UNICAEN, Institut National de la Santé et de la Recherche Médicale U1237, PhIND, Centre Cyceron, Caen 14000, France.
Emergency Department, Caen University Hospital, Caen 14033, France.
J Neurosci. 2020 Feb 19;40(8):1778-1787. doi: 10.1523/JNEUROSCI.0969-19.2019. Epub 2020 Jan 17.
Increase in blood-brain barrier (BBB) permeability is a crucial step in neuroinflammatory processes. We previously showed that N Methyl D Aspartate Receptor (NMDARs), expressed on cerebral endothelial cells forming the BBB, regulate immune cell infiltration across this barrier in the mouse. Here, we describe the mechanism responsible for the action of NMDARs on BBB permeabilization. We report that mouse CNS endothelial NMDARs display the regulatory GluN3A subunit. This composition confers to NMDARs' unconventional properties: these receptors do not induce Ca influx but rather show nonionotropic properties. In inflammatory conditions, costimulation of human brain endothelial cells by NMDA agonists (NMDA or glycine) and the serine protease tissue plasminogen activator, previously shown to potentiate NMDAR activity, induces metabotropic signaling via the Rho/ROCK pathway. This pathway leads to an increase in permeability via phosphorylation of myosin light chain and subsequent shrinkage of human brain endothelial cells. Together, these data draw a link between NMDARs and the cytoskeleton in brain endothelial cells that regulates BBB permeability in inflammatory conditions. The authors describe how NMDARs expressed on endothelial cells regulate blood-brain barrier function via myosin light chain phosphorylation and increase in permeability. They report that these non-neuronal NMDARs display distinct structural, functional, and pharmacological features than their neuronal counterparts.
血脑屏障（BBB）通透性的增加是神经炎症过程中的关键步骤。我们之前曾表明，表达在形成 BBB 的脑内皮细胞上的 N-甲基-D-天冬氨酸受体（NMDAR）调节免疫细胞穿过该屏障在小鼠中的浸润。在这里，我们描述了 NMDAR 对 BBB 通透性作用的机制。我们报告说，小鼠中枢神经系统内皮细胞中的 NMDAR 显示出调节性 GluN3A 亚基。这种组成赋予了 NMDAR 非常规的特性：这些受体不会诱导 Ca2+内流，而是表现出非离子型特性。在炎症条件下，NMDA 激动剂（NMDA 或甘氨酸）和丝氨酸蛋白酶组织纤溶酶原激活物（先前已显示可增强 NMDAR 活性）对人脑血管内皮细胞的共刺激作用，通过 Rho/ROCK 途径诱导代谢型信号转导。该途径通过肌球蛋白轻链的磷酸化和随后的人脑微血管内皮细胞收缩导致通透性增加。这些数据表明，NMDAR 与在炎症条件下调节血脑屏障通透性的脑血管内皮细胞中的细胞骨架之间存在联系。作者描述了表达在内皮细胞上的 NMDAR 如何通过肌球蛋白轻链磷酸化和通透性增加来调节血脑屏障功能。他们报告说，这些非神经元 NMDAR 与神经元 NMDAR 相比具有不同的结构、功能和药理学特征。
