Molecular determinants of NMDA receptor internalization
Abstract
Although synaptic AMPA receptors have been shown to rapidly internalize, synaptic NMDA receptors are reported to be static. It is not certain whether NMDA receptor stability at synaptic sites is an inherent property of the receptor, or is due to stabilization by scaffolding proteins. In this study, we demonstrate that NMDA receptors are internalized in both heterologous cells and neurons, and we define an internalization motif, YEKL, on the distal C-terminus of NR2B. In addition, we show that the synaptic protein PSD-95 inhibits NR2B-mediated internalization, and that deletion of the PDZ-binding domain of NR2B increases internalization in neurons. This suggests an involvement for PSD-95 in NMDA receptor regulation and an explanation for NMDA receptor stability at synaptic sites.
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Surface expression of NMDA receptors is tightly regulated through clathrin-dependent endocytosis and is shown to be endocytosed both in primary neuronal cultures and in vitro heterologous cells.
“The surface expression of NMDA receptors is tightly regulated through clathrin-dependent endocytosis [162,163] and is shown to be endocytosed both in primary neuronal cultures and in vitro heterologous cells [162].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [162]
NMDA receptors play an important role in Aβ-induced neurotoxicity.
“NMDA receptors play an important role in Aβ-induced neurotoxicity [162].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [162]
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- Authors
- Roche, K. W., Standley, S., McCallum, J., Dune Ly, C., Ehlers, M. D., & Wenthold, R. J.
- Affiliations
- National Institutes of Health (US)
- Duke Medical Center (US)
- Corresponding author
- Roche, Katherine W.
- Venue
- Nature Neuroscience
- Published
- 2001-08
- Volume
- 4
- Issue
- 8
- Pages
- 794-802
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1558650798
- Cited by
- 550
- References
- 1
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 16 · 2023: 13 · 2022: 11 · 2021: 14 · 2020: 12 · 2019: 19 · 2018: 9 · 2017: 15 · 2016: 20 · 2015: 20 · 2014: 21 · 2013: 26 · 2012: 23
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Deafness and Other Communication Disorders
- 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 › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- NMDA receptor, receptor internalization, NR2B, PSD-95, PDZ-binding domain, scaffold proteins, AMPA receptor internalization
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Binding Sites, Central Nervous System, Clathrin, Endocytosis, Fetus, HeLa Cells, Hippocampus, Humans, Immunohistochemistry, Membrane Proteins, Nerve Tissue Proteins, Neurons, Recombinant Fusion Proteins, Synaptic Membranes, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Protein Structure, Tertiary, Amino Acid Motifs, Protein Transport, Intracellular Signaling Peptides and Proteins, Rats
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