fmrfamide and lactacystin

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.

Topics: Acetylation; Acetylcysteine; Animals; Aplysia; Cells, Cultured; Coculture Techniques; Cyclic AMP Response Element-Binding Protein; Cysteine Proteinase Inhibitors; Down-Regulation; FMRFamide; Ganglia; Histones; Long-Term Synaptic Depression; Motor Neurons; Nerve Tissue Proteins; Neurons, Afferent; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Promoter Regions, Genetic; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteins; Repressor Proteins; RNA, Messenger; Synapsins; Synaptosomes; Ubiquitin; Ubiquitin Thiolesterase; Ubiquitination; Up-Regulation