期刊
JOURNAL OF NEUROSCIENCE
卷 33, 期 33, 页码 13398-13409出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.6255-11.2013
关键词
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资金
- German Research Foundation through the Cluster of Excellence
- Collaborative Research Center [889]
- German Research Foundation [SCHL592/4]
- European Commission through the Marie Curie initial training network SyMBaD
- Alexander von Humboldt Foundation
- National Institutes of Health/National Institute on Drug Abuse [DA030379, DA023206, DA031551, DA034856]
- Gottingen University Medical School
- Max Planck Society
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.
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