Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Abstract

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.endoplasmic reticulum degradation pathway ͉ neuronal activity ͉ NFB42 ͉ proteasome ͉ ubiquitylation

Selective Cochlear Degeneration in Mice Lacking the F-Box Protein, Fbx2, a Glycoprotein-Specific Ubiquitin Ligase Subunit

“…We also confirmed the interaction of Fbx2 with a recently identified substrate glycoprotein in brain, the NR1 subunit of the NMDA receptor (Fig. 6b) (Kato et al, 2005).…”

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

“…66 However, from the present data it cannot be determined if the increased ratio of NR1 C2 0 /NR1 C2 in schizophrenia causes changes in ER assembly of the NMDA receptor, or whether this increased amount of NR1 C2 0 in the complete NR1 pool, which is already expressed in surplus in the ER, is degraded through the endogenous ERAD mechanism. 4,5 Future studies on how NR1 splice variants are recruited for receptor assembly or degradation in the ER are needed to further understand the implications of our finding.…”

“…3 Contrary to the expression of the NR2 subunits, the NR1 subunit is normally expressed in excess in the endoplasmatic reticulum (ER) where it, when unassembled, is degraded by an activity-dependent process known as ER-associated degradation (ERAD). 4,5 Assembly of NR1 isoforms with different NR2 subunits determines essential functional attributes, including synaptic targeting, modulation of channel gating and receptor interaction with intracellular signaling proteins. [6][7][8][9][10][11] Inclusion of different alternative splice variants of the NR1 subunit confers different intracellular interactions that affect receptor signaling and transport.…”

The ubiquitin-proteasome pathway and synaptic plasticity

“…The NMDA receptors are retrotranslocated and degraded by the UPP in an activity-dependent fashion. An F-box protein called Fbx2 is critical for this process (Kato et al 2005), suggesting that an SCF-type ligase targets the NMDA receptors for ubiquitination. Endocytosis of other neurotransmitter receptors might be regulated by ubiquitination.…”