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Synaptic state-dependent functional interplay between postsynaptic density-95 and synapse-associated protein 102.

Abstract
Activity-dependent regulation of AMPA receptor (AMPAR)-mediated synaptic transmission is the basis for establishing differences in synaptic weights among individual synapses during developmental and experience-dependent synaptic plasticity. Synaptic signaling scaffolds of the Discs large (DLG)-membrane-associated guanylate kinase (MAGUK) protein family regulate these processes by tethering signaling proteins to receptor complexes. Using a molecular replacement strategy with RNAi-mediated knockdown in rat and mouse hippocampal organotypic slice cultures, a postsynaptic density-95 (PSD-95) knock-out mouse line and electrophysiological analysis, our current study identified a functional interplay between two paralogs, PSD-95 and synapse-associated protein 102 (SAP102) to regulate synaptic AMPARs. During synaptic development, the SAP102 protein levels normally plateau but double if PSD-95 expression is prevented during synaptogenesis. For an autonomous function of PSD-95 in regulating synaptic AMPARs, in addition to the previously demonstrated N-terminal multimerization and the first two PDZ (PSD-95, Dlg1, zona occludens-1) domains, the PDZ3 and guanylate kinase domains were required. The Src homology 3 domain was dispensable for the PSD-95-autonomous regulation of basal synaptic transmission. However, it mediated the functional interaction with SAP102 of PSD-95 mutants to enhance AMPARs. These results depict a protein domain-based multifunctional aspect of PSD-95 in regulating excitatory synaptic transmission and unveil a novel form of domain-based interplay between signaling scaffolds of the DLG-MAGUK family.
AuthorsStéphanie A D Bonnet, Derya S Akad, Tanmoy Samaddar, Yanling Liu, Xiaojie Huang, Yan Dong, Oliver M Schlüter
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 33 Issue 33 Pg. 13398-409 (Aug 14 2013) ISSN: 1529-2401 [Electronic] United States
PMID23946397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Disks Large Homolog 4 Protein
  • Dlg3 protein, rat
  • Dlg4 protein, mouse
  • Dlg4 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neuropeptides
  • Dlgh3 protein, mouse
  • Guanylate Kinases
Topics
  • Animals
  • Blotting, Western
  • Disks Large Homolog 4 Protein
  • Female
  • Gene Knockout Techniques
  • Guanylate Kinases (metabolism)
  • Intracellular Signaling Peptides and Proteins (metabolism)
  • Male
  • Membrane Proteins (metabolism)
  • Mice
  • Neuropeptides (metabolism)
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Rats
  • Rats, Wistar
  • Synapses (metabolism)
  • Synaptic Transmission (physiology)

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