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Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5600-5. Epub 2005 Apr 4.

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination.

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  • 1Department of Physiology, University of California-San Francisco, 600 16th Street, San Francisco, CA 94143, USA.


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.

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