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Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization.
Mol Pharmacol. 2006 Apr; 69(4):1251-9.MP

Abstract

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) activity regulates the net number of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) at the cell surface by modulating the balance between AMPAR membrane insertion and endocytosis. In this study, we addressed the role of NMDAR subtypes and of NMDAR-mediated Ca2+ influx in the NMDAR-induced endocytosis of GluR2-containing AMPARs in primary murine hippocampal neurons. We found that NMDAR activation enhanced the endocytosis of AMPARs containing the GluR2 splice variants with short, but not long, cytoplasmic tails. NMDA-induced GluR2 endocytosis was completely inhibited by pharmacological block of NR2B-containing NMDARs. In turn, preferential block of NR2A-containing NMDARs did not affect NMDA-induced AMPAR endocytosis, indicating that AMPAR internalization is controlled by a restricted set of NMDARs. The NMDA-induced GluR2 internalization was also observed in the absence of extracellular Na+ ions, suggesting that membrane depolarization is not a prerequisite for this effect. Furthermore, the activation of Ca2+-impermeable NMDARs containing the mutant NR1(N598R) subunit failed to enhance AMPAR endocytosis, indicating a requirement of Ca2+ influx directly through the NMDAR channels. In summary, our findings suggest that the NMDAR-induced selective internalization of short C-terminal GluR2-containing AMPARs requires a Ca2+ signal that originates from NMDAR channels and is processed in an NMDAR subtype-restricted manner.

Authors+Show Affiliations

Tigaret CM
Laboratory for Molecular Pharmacology, Department of Pharmacology, UCL, Gower Street, London WC1E 6BT, UK.
Thalhammer A
No affiliation info available
Rast GF
No affiliation info available
Specht CG
No affiliation info available
Auberson YP
No affiliation info available
Stewart MG
No affiliation info available
Schoepfer R
No affiliation info available

MeSH

AnimalsBase SequenceDNA PrimersEndocytosisGreen Fluorescent ProteinsHippocampusMiceNeuronsPhenotypeReceptors, AMPAReceptors, N-Methyl-D-Aspartate

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16436589

Citation

Tigaret, C M., et al. "Subunit Dependencies of N-methyl-D-aspartate (NMDA) Receptor-induced Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization." Molecular Pharmacology, vol. 69, no. 4, 2006, pp. 1251-9.
Tigaret CM, Thalhammer A, Rast GF, et al. Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. Mol Pharmacol. 2006;69(4):1251-9.
Tigaret, C. M., Thalhammer, A., Rast, G. F., Specht, C. G., Auberson, Y. P., Stewart, M. G., & Schoepfer, R. (2006). Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. Molecular Pharmacology, 69(4), 1251-9.
Tigaret CM, et al. Subunit Dependencies of N-methyl-D-aspartate (NMDA) Receptor-induced Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization. Mol Pharmacol. 2006;69(4):1251-9. PubMed PMID: 16436589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. AU - Tigaret,C M, AU - Thalhammer,A, AU - Rast,G F, AU - Specht,C G, AU - Auberson,Y P, AU - Stewart,M G, AU - Schoepfer,R, Y1 - 2006/01/25/ PY - 2006/1/27/pubmed PY - 2006/6/20/medline PY - 2006/1/27/entrez SP - 1251 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 69 IS - 4 N2 - N-Methyl-D-aspartate (NMDA) receptor (NMDAR) activity regulates the net number of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) at the cell surface by modulating the balance between AMPAR membrane insertion and endocytosis. In this study, we addressed the role of NMDAR subtypes and of NMDAR-mediated Ca2+ influx in the NMDAR-induced endocytosis of GluR2-containing AMPARs in primary murine hippocampal neurons. We found that NMDAR activation enhanced the endocytosis of AMPARs containing the GluR2 splice variants with short, but not long, cytoplasmic tails. NMDA-induced GluR2 endocytosis was completely inhibited by pharmacological block of NR2B-containing NMDARs. In turn, preferential block of NR2A-containing NMDARs did not affect NMDA-induced AMPAR endocytosis, indicating that AMPAR internalization is controlled by a restricted set of NMDARs. The NMDA-induced GluR2 internalization was also observed in the absence of extracellular Na+ ions, suggesting that membrane depolarization is not a prerequisite for this effect. Furthermore, the activation of Ca2+-impermeable NMDARs containing the mutant NR1(N598R) subunit failed to enhance AMPAR endocytosis, indicating a requirement of Ca2+ influx directly through the NMDAR channels. In summary, our findings suggest that the NMDAR-induced selective internalization of short C-terminal GluR2-containing AMPARs requires a Ca2+ signal that originates from NMDAR channels and is processed in an NMDAR subtype-restricted manner. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16436589/Subunit_dependencies_of_N_methyl_D_aspartate__NMDA__receptor_induced_alpha_amino_3_hydroxy_5_methyl_4_isoxazolepropionic_acid__AMPA__receptor_internalization_ DB - PRIME DP - Unbound Medicine ER -