title: Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II.
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.
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0347, USA.
authors.forename: Stevan N
authors.initials: SN
authors.lastname: Djakovic
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Schwarz
authors.forename: Barbara
authors.initials: B
authors.lastname: Barylko
authors.forename: George N
authors.initials: GN
authors.lastname: DeMartino
authors.forename: Gentry N
authors.initials: GN
authors.lastname: Patrick
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D026941:Sodium Channel Blockers; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D046988:Proteasome Endopeptidase Complex; D002118:Calcium