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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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Figure 1: Full-length NR2B/NR1 complexes are internalized in HeLa cells.
Figure 2: The distal C-terminus of NR2B (1315–1482).
Figure 3: A tyrosine motif within the NR2B C-terminus regulates internalization of the TacNR2B chimera to endosomes.
Figure 4: TacNR2B internalization is dynamin-dependent.
Figure 5: Endogenous NMDA receptors undergo endocytosis, which decreases during development.
Figure 6: PSD-95 inhibits internalization of TacNR2B and clusters it on the cell surface.
Figure 7: TacNR2B internalization in neurons is regulated by the PDZ-binding domain.

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Acknowledgements

This work was supported by the NIDCD intramural program, and in part by grants from National Institutes of Health (RO1-NS39402) and the Spinal Cord Research Foundation (to M.D.E.).

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Correspondence to Katherine W. Roche.

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Roche, K., Standley, S., McCallum, J. et al. Molecular determinants of NMDA receptor internalization. Nat Neurosci 4, 794–802 (2001). https://doi.org/10.1038/90498

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