Abstract
The neuropeptide Phe-Met-Arg-Phe-NH(2) (FMRFa) can induce transcription-dependent long-term synaptic depression (LTD) in Aplysia sensorimotor synapses. We investigated the role of the ubiquitin-proteasome system and the regulation of one of its components, ubiquitin C-terminal hydrolase (ap-uch), in LTD. LTD was sensitive to presynaptic inhibition of the proteasome and was associated with upregulation of ap-uch mRNA and protein. This upregulation appeared to be mediated by CREB2, which is generally regarded as a transcription repressor. Binding of CREB2 to the promoter region of ap-uch was accompanied by histone hyperacetylation, suggesting that CREB2 cannot only inhibit but also promote gene expression. CREB2 was phosphorylated after FMRFa, and blocking phospho-CREB2 blocked LTD. In addition to changes in the expression of ap-uch, the synaptic vesicle-associated protein synapsin was downregulated in LTD in a proteasome-dependent manner. These results suggest that proteasome-mediated protein degradation is engaged in LTD and that CREB2 may act as a transcription activator under certain conditions.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylation
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Acetylcysteine / analogs & derivatives
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Acetylcysteine / pharmacology
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Animals
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Aplysia / physiology*
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Cells, Cultured
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Coculture Techniques
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cysteine Proteinase Inhibitors / pharmacology
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Down-Regulation
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FMRFamide / pharmacology
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Ganglia / cytology
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Ganglia / metabolism
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Histones / metabolism
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology*
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Motor Neurons / physiology
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Nerve Tissue Proteins / metabolism
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Neurons, Afferent / physiology
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Phosphorylation
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Promoter Regions, Genetic
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Inhibitors
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Proteins / metabolism
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RNA, Messenger / metabolism
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Repressor Proteins / metabolism
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Synapsins / metabolism
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Synaptosomes / metabolism
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Ubiquitin / metabolism*
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism
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Ubiquitination / drug effects
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ApCREB2 protein, Aplysia californica
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Cyclic AMP Response Element-Binding Protein
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Cysteine Proteinase Inhibitors
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Histones
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Nerve Tissue Proteins
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Proteasome Inhibitors
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Proteins
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RNA, Messenger
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Repressor Proteins
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Synapsins
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Ubiquitin
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lactacystin
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FMRFamide
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p38 Mitogen-Activated Protein Kinases
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Ubiquitin Thiolesterase
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Proteasome Endopeptidase Complex
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Acetylcysteine