The synaptic scaffold protein MPP2 interacts with GABAA receptors at the periphery of the postsynaptic density of glutamatergic synapses

PLoS Biol. 2022 Mar 21;20(3):e3001503. doi: 10.1371/journal.pbio.3001503. eCollection 2022 Mar.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Membrane Proteins* / metabolism
  • Post-Synaptic Density* / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, GABA-A
  • Synapses / metabolism

Substances

  • Membrane Proteins
  • Receptors, AMPA
  • Receptors, GABA-A

Grants and funding

This work was primarily supported by grants from the ‘Deutsche Forschungsgemeinschaft’ (DFG), including project numbers 261102178 (grant recipient SAS) and 431572356 (grant recipients SAS and DS), and the DFG Collaborative Research Centers SFB 958 (grant recipients SAS, HE, CF, and JS) and TRR 186 (DFG project number 278001972; grant recipient HE). Further financial support was provided by the DFG-funded NeuroCure Cluster of Excellence (EXC 2049; grant recipient DS). BS was additionally funded by a Charité PhD fellowship (‘Promotionsabschlussstipendium’). For mass spectrometry, we would like to acknowledge the assistance of the Core Facility BioSupraMol, which is supported by the DFG. For fluorescence imaging we would like to acknowledge the assistance of the Core Facility AMBIO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.