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.