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J. Biol. Chem., Vol. 282, Issue 24, 17594-17607, June 15, 2007

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N-Methyl-D-aspartate Receptor-dependent Regulation of the Glutamate Transporter Excitatory Amino Acid Carrier 1^*

Elisa A. Waxman, Isabelle Baconguis^¶, David R. Lynch^¶12, and Michael B. Robinson^¶1

From the Departments of Pharmacology, Neurology, and ^¶Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

The neuronal transporter excitatory amino acid carrier 1 (EAAC1) is enriched in perisynaptic regions, where it may regulate synaptic spillover of glutamate. In this study we examined potential interactions between EAAC1 and ionotropic glutamate receptors. N-Methyl-D-aspartate (NMDA) receptor subunits NR1, NR2A, and NR2B, but not the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluR2, were co-immunoprecipitated with EAAC1 from neuron-enriched hippocampal cultures. A similar interaction was observed in C6 glioma and human embryonic kidney cells after co-transfection with Myc epitope-tagged EAAC1 and NMDA receptor subunits. Co-transfection of C6 glioma with the combination of NR1 and NR2 subunits dramatically increased (3-fold) the amount of Myc-EAAC1 that can be labeled with a membrane-impermeable biotinylating reagent. In hippocampal cultures, brief (5 min), robust (100 µM NMDA, 10 µM glycine) activation of the NMDA receptor decreased biotinylated EAAC1 to 50% of control levels. This effect was inhibited by an NMDA receptor antagonist, intracellular or extracellular calcium chelators, or hypertonic sucrose. Glutamate, -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid with cyclothiazide, and thapsigargin mimicked the effects of NMDA. These studies suggest that NMDA receptors interact with EAAC1, facilitate cell surface expression of EAAC1 under basal conditions, and control internalization of EAAC1 upon activation. This NMDA receptor-dependent regulation of EAAC1 provides a novel mechanism that may shape excitatory signaling during synaptic plasticity and/or excitotoxicity.

Received for publication, March 15, 2007 , and in revised form, April 19, 2007.

^* This work was supported by National Institutes of Health Grants NS39011 (to M. B. R.) and NS45986 (to D. R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 502 Abramson Bldg., Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104. Tel.: 215-590-2242; Fax: 215-590-3779; E-mail: lynch{at}pharm.med.upenn.edu.

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