Activity Level Controls Postsynaptic Composition and Signaling via the Ubiquitin-Proteasome System

Nat Neurosci. 2003 Mar;6(3):231-42. doi: 10.1038/nn1013.

Abstract

Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase-MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Carrier Proteins / analysis
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Hippocampus / cytology
  • Mitogen-Activated Protein Kinases / metabolism
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / metabolism
  • Proteasome Endopeptidase Complex
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Signal Transduction / physiology*
  • Synapses / chemistry
  • Synapses / metabolism*
  • Synaptic Transmission / physiology*
  • Ubiquitin / metabolism*

Substances

  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing
  • Akap5 protein, rat
  • Carrier Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Ubiquitin
  • postsynaptic density proteins
  • Mitogen-Activated Protein Kinases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex