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Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons.

Cyclin-dependent kinase 5 (Cdk5) and its activator p35 have been implicated in drug addiction, neurodegenerative diseases such as Alzheimer's, learning and memory, and synapse maturation and plasticity. However, the molecular mechanisms by which Cdk5 regulates synaptic plasticity are still unclear. PSD-95 is a major postsynaptic scaffolding protein of glutamatergic synapses that regulates synaptic strength and plasticity. PSD-95 is ubiquitinated by the ubiquitin E3 ligase Mdm2, and rapid and transient PSD-95 ubiquitination has been implicated in NMDA receptor-induced AMPA receptor endocytosis. Here we demonstrate that genetic or pharmacological reduction of Cdk5 activity increases the interaction of Mdm2 with PSD-95 and enhances PSD-95 ubiquitination without affecting PSD-95 protein levels in vivo in mice, suggesting a nonproteolytic function of ubiquitinated PSD-95 at synapses. We show that PSD-95 ubiquitination correlates with increased interaction with β-adaptin, a subunit of the clathrin adaptor protein complex AP-2. This interaction is increased by genetic reduction of Cdk5 activity or NMDA receptor stimulation and is dependent on Mdm2. Together these results support a function for Cdk5 in regulating PSD-95 ubiquitination and its interaction with AP-2 and suggest a mechanism by which PSD-95 may regulate NMDA receptor-induced AMPA receptor endocytosis.

Pubmed ID: 21849563 RIS Download

Mesh terms: Animals | Cyclin-Dependent Kinase 5 | Female | Guanylate Kinases | Hippocampus | Male | Membrane Proteins | Mice | Mice, Knockout | Neurons | Organ Culture Techniques | Protein Interaction Mapping | Ubiquitination

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Associated grants

  • Agency: NIDA NIH HHS, Id: 1P30DA018343
  • Agency: NCI NIH HHS, Id: R01 CA077735
  • Agency: NIDA NIH HHS, Id: R01 DA019451-05
  • Agency: NIDA NIH HHS, Id: P30 DA018343
  • Agency: NIDA NIH HHS, Id: R01 DA019451
  • Agency: NIDA NIH HHS, Id: R01DA019451
  • Agency: NCI NIH HHS, Id: R01CA077735
  • Agency: NCI NIH HHS, Id: R01 CA077735-12

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