Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II

Stevan N. Djakovic, Lindsay A. Schwarz, Barbara Barylko, George N. DeMartino, Gentry N. Patrick

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Protein degradation via the ubiquitin proteasome system has been shown to regulate changes in synaptic strength that underlie multiple forms of synaptic plasticity. It is plausible, therefore, that the ubiquitin proteasome system is itself regulated by synaptic activity. By utilizing live-cell imaging strategies we report the rapid and dynamic regulation of the proteasome in hippocampal neurons by synaptic activity. We find that the blockade of action potentials (APs) with tetrodotoxin inhibited the activity of the proteasome, whereas the up-regulation of APs with bicuculline dramatically increased the activity of the proteasome. In addition, the regulation of the proteasome is dependent upon external calcium entry in part through N-methyl-D-aspartate receptors and L-type voltage-gated calcium channels and requires the activity of calcium/ calmodulin-dependent protein kinase II (CaMKII). Using in vitro and in vivo assays we find that CaMKII stimulates proteasome activity and directly phosphorylates Rpt6, a subunit of the 19 S (PA700) subcomplex of the 26 S proteasome. Our data provide a novel mechanism whereby CaMKII may regulate the proteasome in neurons to facilitate remodeling of synaptic connections through protein degradation.

Original languageEnglish (US)
Pages (from-to)26655-26665
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number39
DOIs
StatePublished - Sep 25 2009

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Proteasome Endopeptidase Complex
Ubiquitin
Proteolysis
Action Potentials
Neurons
Degradation
Neuronal Plasticity
Bicuculline
Tetrodotoxin
Calcium Channels
N-Methyl-D-Aspartate Receptors
Plasticity
Assays
Proteins
Up-Regulation
Calcium
Imaging techniques

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II. / Djakovic, Stevan N.; Schwarz, Lindsay A.; Barylko, Barbara; DeMartino, George N.; Patrick, Gentry N.

In: Journal of Biological Chemistry, Vol. 284, No. 39, 25.09.2009, p. 26655-26665.

Research output: Contribution to journalArticle

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