Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination.
The extracellular N-terminal domain (NTD) is the largest region of NMDA receptors; however, biological roles for this ectodomain remain unknown. Here, we determined that the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain. F-box proteins specify ubiquitination by linking protein substrates to the terminal E3 ligase. Indeed, ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant. When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion. These results suggest that homeostatic control of synaptic NR1 involves receptor retrotranslocation and degradation by the ubiquitin-proteasome pathway.
Kato
Akihiko
A
Department of Physiology, University of California-San Francisco, 600 16th Street, San Francisco, CA 94143, USA.
Rouach
Nathalie
N
Nicoll
Roger A
RA
Bredt
David S
DS
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003712:Dendrites / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008358:Mannose / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D044783:F-Box Proteins; C500719:Fbx2 protein, mouse; D011134:Polysaccharides; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D008358:Mannose