The ubiquitin-proteasome system is necessary for long-term synaptic depression in Aplysia

J Neurosci. 2008 Oct 8;28(41):10245-56. doi: 10.1523/JNEUROSCI.2139-08.2008.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Acetylcysteine / analogs & derivatives
  • Acetylcysteine / pharmacology
  • Animals
  • Aplysia / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Down-Regulation
  • FMRFamide / pharmacology
  • Ganglia / cytology
  • Ganglia / metabolism
  • Histones / metabolism
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Motor Neurons / physiology
  • Nerve Tissue Proteins / metabolism
  • Neurons, Afferent / physiology
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Proteins / metabolism
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism
  • Synapsins / metabolism
  • Synaptosomes / metabolism
  • Ubiquitin / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination / drug effects
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ApCREB2 protein, Aplysia californica
  • Cyclic AMP Response Element-Binding Protein
  • Cysteine Proteinase Inhibitors
  • Histones
  • Nerve Tissue Proteins
  • Proteasome Inhibitors
  • Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Synapsins
  • Ubiquitin
  • lactacystin
  • FMRFamide
  • p38 Mitogen-Activated Protein Kinases
  • Ubiquitin Thiolesterase
  • Proteasome Endopeptidase Complex
  • Acetylcysteine