Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Germany.
Advanced Medical BioImaging Core Facility-AMBIO, Charité-Universitätsmedizin Berlin, Germany.
PLoS Biol. 2022 Mar 21;20(3):e3001503. doi: 10.1371/journal.pbio.3001503. eCollection 2022 Mar.
Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in subsynaptic nanodomains. The synaptic membrane-associated guanylate kinase (MAGUK) scaffold protein membrane protein palmitoylated 2 (MPP2) is a component of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM 1. Using superresolution imaging, we show that-like SynCAM 1-MPP2 is situated at the periphery of the postsynaptic density (PSD). In order to explore MPP2-associated protein complexes, we used a quantitative comparative proteomics approach and identified multiple γ-aminobutyric acid (GABA)A receptor subunits among novel synaptic MPP2 interactors. In line with a scaffold function for MPP2 in the assembly and/or modulation of intact GABAA receptors, manipulating MPP2 expression had effects on inhibitory synaptic transmission. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold that serves as an adaptor molecule, linking peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses.
成像技术的最新进展强调了支架蛋白和受体在亚突触纳米域中排列。突触膜相关鸟苷酸激酶（MAGUK）支架蛋白棕榈酰化 2（MPP2）是α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体相关蛋白复合物的组成部分，也与突触细胞粘附分子 SynCAM 1 结合。使用超分辨率成像，我们表明类似于 SynCAM 1，MPP2位于突触后密度（PSD）的外围。为了探索与 MPP2 相关的蛋白复合物，我们使用定量比较蛋白质组学方法鉴定出新型突触 MPP2 相互作用蛋白中的多个γ-氨基丁酸（GABA）A 受体亚基。与 MPP2 在完整 GABA A 受体的组装和/或调节中的支架功能一致，操纵 MPP2 的表达会影响抑制性突触传递。我们进一步表明，GABA A 受体与 MPP2 一起存在于树突棘的亚群中，因此突出了 MPP2 作为一种支架分子，将谷氨酸能突触 PSD 中对抑制调节至关重要的外围突触元件与中央结构连接起来。
