Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.
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.
Ehlers
Michael D
MD
Department of Neurobiology, Box 3209, Duke University Medical Center, Durham, North Carolina 27710, USA. ehlers@neuro.duke.edu
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000737:chemistry / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D025801:Ubiquitin; C033652:postsynaptic density proteins; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex