17 Schmerl, Bettina Gimber, Niclas Kuropka, Benno Stumpf, Alexander Rentsch, Jakob Kunde, Stella-Amrei von Sivers, Judith Ewers, Helge Schmitz, Dietmar Freund, Christian Schmoranzer, Jan Rademacher, Nils Shoichet, Sarah A AG Schmitz 1 AG Garner PLoS biology PLoS biology PLoS Lawrence, KS 1544-9173 10.1371/journal.pbio.3001503 English e3001503 3 20 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. PUB:(DE-HGF)16, ; 0, ; Membrane Proteins: metabolism Post-Synaptic Density: metabolism Receptors, AMPA: metabolism Receptors, GABA-A Synapses: metabolism Membrane Proteins Receptors, AMPA Receptors, GABA-A Journal Article 2022 DZNE-2022-00481 2022 pmc:PMC8970474 pmid:35312684 https://pub.dzne.de/record/163742 https://doi.org/10.1371/journal.pbio.3001503