Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Rep. 2019 Jul 9;28(2):332-341.e5. doi: 10.1016/j.celrep.2019.06.030.
In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.
在成熟的神经元中，突触后 N-甲基-D-天冬氨酸受体（NMDAR）分为突触内和突触外两种群体，它们在定位、功能和相关的细胞内级联反应方面存在差异。这两个池通过侧向扩散连接，它们之间的受体交换调节突触 NMDAR 含量。在这里，我们确定 NMDAR 中 GluN2B 亚基 PDZ 配体的磷酸化（在 S1480 处）是动态控制 NMDAR 突触含量的关键决定因素。我们发现，在 S1480 处磷酸化的 GluN2B 将 NMDAR 保持在突触外膜上，作为包含蛋白磷酸酶 1（PP1）的蛋白质复合物的一部分。全局激活 NMDAR 会导致 PP1 的激活，从而介导 GluN2B 在 S1480 处的去磷酸化，从而促进突触 NMDAR 含量的增加。因此，PP1 介导的 GluN2B PDZ 配体去磷酸化以依赖于活动的方式调节成熟神经元中 NMDAR 的突触表达，这一过程对突触和结构可塑性、超可塑性和突触神经传递具有深远的影响。
