2001
DOI: 10.1523/jneurosci.21-09-03063.2001
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An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing

Abstract: Formation of mature excitatory synapses requires the assembly and delivery of NMDA receptors to the neuronal plasma membrane. A key step in the trafficking of NMDA receptors to synapses is the exit of newly assembled receptors from the endoplasmic reticulum (ER). Here we report the identification of an RXR-type ER retention/retrieval motif in the C-terminal tail of the NMDA receptor subunit NR1 that regulates receptor surface expression in heterologous cells and in neurons. In addition, we show that PKC phosph… Show more

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Cited by 387 publications
(358 citation statements)
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“…In the presence of the NR2B subunit, however, the NR1-D 1 receptor complex was completely translocated to the plasma membrane. These observations are consistent with previous data showing that, when expressed alone in both heterologous cells and cultured hippocampal neurons, the NR1 subunit accumulates in the ER (19,30) due to the presence of an ER retention motif in the alternatively spliced C1 domain in its C terminus (38) and that coexpression of NR2 subunits is necessary to drive the complex to the cell membrane (19,30). Taken together, these data suggest that, in striatal medium spiny neurons, D 1 and NMDA receptors are assembled within intracellular compartments as constitutive heteromeric complexes that are delivered to functional sites.…”
Section: Discussionsupporting
confidence: 93%
“…In the presence of the NR2B subunit, however, the NR1-D 1 receptor complex was completely translocated to the plasma membrane. These observations are consistent with previous data showing that, when expressed alone in both heterologous cells and cultured hippocampal neurons, the NR1 subunit accumulates in the ER (19,30) due to the presence of an ER retention motif in the alternatively spliced C1 domain in its C terminus (38) and that coexpression of NR2 subunits is necessary to drive the complex to the cell membrane (19,30). Taken together, these data suggest that, in striatal medium spiny neurons, D 1 and NMDA receptors are assembled within intracellular compartments as constitutive heteromeric complexes that are delivered to functional sites.…”
Section: Discussionsupporting
confidence: 93%
“…The PSD-95 homologue SAP102 also binds to NMDA receptors and colocalizes with them at postsynaptic sites (35,45,55). In addition, SAP102 may interact with the NMDA receptor in the endoplasmic reticulum, and such an interaction may be necessary for the release of the NMDA receptor from this compartment (53,54). At variance with PSD-95, a large portion of SAP102 is effectively solubilized by Triton X-100 and coimmunoprecipitates with the immature NR1 from Triton X-100 extracts.…”
Section: Discussionmentioning
confidence: 99%
“…A reduction in the number of synapses should therefore be accompanied by a decrease in either total PSD-95 levels (caused by backlog and degradation) or the degree of its association with NMDA receptors if backlogged PSD-95 is not effectively degraded. Homologs of PSD-95 may associate with their targets in the endoplasmic reticulum (52), and such an association may be important for releasing NMDA receptor complexes from this compartment (53,54). One candidate that may fulfill this function is SAP102 (54).…”
Section: Evaluation Of Potential Changes Of Synaptic or Dendritic Strmentioning
confidence: 99%
“…Levels of NMDA receptors in prefrontal cortex, striatum and hippocampus of wild-type and NR1-KD mice were assessed by western blot analysis, and revealed that NR2A and NR2B subunits of the NMDA receptor were also substantially reduced to approximately 10-20% as a consequence of NR1 deficiency (Figure 1). Normally the NR1 subunit is present in excess and is retained in the ER or rapidly degraded when not assembled with an NR2 subunit (Huh and Wenthold, 1999;Scott et al, 2001). In the NR1-KD mice, the NR1 subunit must be the limiting factor in the assembly of heteromeric NMDA receptors.…”
Section: Glutamate Receptor Levels In Various Brain Regions Of Nr1-kdmentioning
confidence: 99%