Abstract
Little is known about how synaptic activity is modulated in the central nervous system. We have identified SCRAPPER, a synapse-localized E3 ubiquitin ligase, which regulates neural transmission. SCRAPPER directly binds and ubiquitinates RIM1, a modulator of presynaptic plasticity. In neurons from Scrapper-knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation. As anticipated in a RIM1 degradation defect mutant, SCR-KO mice displayed altered electrophysiological synaptic activity, i.e., increased frequency of miniature excitatory postsynaptic currents. This phenotype of SCR-KO mice was phenocopied by RIM1 overexpression and could be rescued by re-expression of SCRAPPER or knockdown of RIM1. The acute effects of proteasome inhibitors, such as upregulation of RIM1 and the release probability, were blocked by the impairment of SCRAPPER. Thus, SCRAPPER has an essential function in regulating proteasome-mediated degradation of RIM1 required for synaptic tuning.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / cytology
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Brain / drug effects
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Brain / enzymology
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Brain / metabolism*
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Excitatory Postsynaptic Potentials
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F-Box Proteins
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GTP-Binding Proteins / deficiency
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Genotype
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Half-Life
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Kinetics
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Leupeptins / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Nerve Tissue Proteins
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Neuronal Plasticity
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Neurons / enzymology
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Neurons / metabolism
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Phenotype
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Presynaptic Terminals / enzymology
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Presynaptic Terminals / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Processing, Post-Translational*
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Synapses / drug effects
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Synapses / enzymology
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Synapses / metabolism*
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Synaptic Transmission* / drug effects
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Synaptic Vesicles / drug effects
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Synaptic Vesicles / metabolism*
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Transfection
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligase Complexes
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Enzyme Inhibitors
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F-Box Proteins
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Fbxl20 protein, mouse
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Leupeptins
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Nerve Tissue Proteins
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Proteasome Inhibitors
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RNA, Messenger
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Rims1 protein, mouse
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Ubiquitin
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Ubiquitin-Protein Ligase Complexes
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Ubiquitin-Protein Ligases
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Proteasome Endopeptidase Complex
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GTP-Binding Proteins
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde