An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing
Open accessAbstract
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 phosphorylation and an alternatively spliced consensus type I PDZ-binding domain suppress ER retention. These results demonstrate a novel quality control function for alternatively spliced C-terminal domains of NR1 and implicate both phosphorylation and potential PDZ-mediated interactions in the trafficking of NMDA receptors through early stages of the secretory pathway.
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- Authors
- Scott, D. B., Blanpied, T. A., Swanson, G. T., Zhang, C., & Ehlers, M. D.
- Affiliations
- Duke Medical Center (US)
- Salk Institute for Biological Studies (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-05-01
- Volume
- 21
- Issue
- 9
- Pages
- 3063-3072
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762585
- OpenAlex
- W1527134354
- Cited by
- 418
- References
- 62
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 10 · 2016: 3 · 2015: 12 · 2014: 13 · 2013: 10 · 2012: 10
- FWCI
- 12.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alfred P. Sloan Foundation
- American Health Assistance Foundation
- McKnight Foundation
- North Carolina Biotechnology Center
- Triangle Community Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01 NS39402, R01NS039402)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- NMDA receptor, NR1 subunit, endoplasmic reticulum retention signal, PKC phosphorylation, alternative splicing, PDZ-binding domain, receptor surface expression, excitatory synapse formation, secretory pathway, quality control, receptor trafficking
- MeSH terms
- Animals, Cells, Cultured, Endoplasmic Reticulum, Hippocampus, Humans, Neurons, Phosphorylation, Protein Kinase C, Recombinant Fusion Proteins, Transcription Factors, Transfection, Receptors, Interleukin-2, Receptors, N-Methyl-D-Aspartate, Alternative Splicing, Protein Structure, Tertiary, Receptors, Retinoic Acid, Amino Acid Motifs, Protein Subunits, Protein Sorting Signals, Retinoid X Receptors, Rats
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