Synaptic state-dependent functional interplay between postsynaptic density-95 and synapse-associated protein 102.
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.
Molecular Neurobiology and Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain, European Neuroscience Institute, D-37077 Göttingen, Germany.
Stéphanie A D
SA
Bonnet
Derya S
DS
Akad
Tanmoy
T
Samaddar
Yanling
Y
Liu
Xiaojie
X
Huang
Yan
Y
Dong
Oliver M
OM
Schlüter
D000818:Animals; D015153:Blotting, Western; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D055786:Gene Knockout Techniques; D051528:Guanylate Kinases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D000076122:Disks Large Homolog 4 Protein; C101195:Dlg3 protein, rat; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases