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J. Biol. Chem., Vol. 282, Issue 35, 25299-25307, August 31, 2007

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N-Methyl-D-aspartate (NMDA) Receptor Subunit NR1 Forms the Substrate for Oligomeric Assembly of the NMDA Receptor^*

Palmi T. Atlason, Molly L. Garside, Elisabeth Meddows^¶, Paul Whiting^¶, and R. A. Jeffrey McIlhinney¹

From the MRC Anatomical Neuropharmacology Unit, Mansfield Road, Oxford OX1 3TH, ^¶Merck Sharp & Dohme Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, and the School of Biological Sciences, Royal Holloway College, University of London, Egham TW20 0EX, United Kingdom

The time course of the assembly of the N-methyl-D-aspartate receptor was examined in a cell line expressing it under the control of the dexamethasone promoter. These studies suggested a delay between the appearance of the NR1 and NR2A subunits and their stable association as examined by co-immunoprecipitation of NR1 and NR2A. This prompted us to examine the stability and folding of the individual subunits using nonreduced polyacrylamide gels and the sulfhydryl cross-linker BMH. Both studies showed that the NR1 subunit was expressed in a monomer and dimer form, whereas both NR2 and NR3 showed substantial aggregation on both nonreduced gels and after cross-linking. Protein degradation experiments showed that NR1 was relatively stable, whereas NR2 and NR3 were more rapidly degraded. When co-expressed with NR1, NR2 was more stable. Fluorescence recovery after photobleaching experiments showed that, under conditions of reduced ATP, the diffusion rate of NR2 and NR3 in the endoplasmic reticulum was reduced, whereas that of NR1 was unaffected. Together these data show that NR1 folds stably when expressed alone, unlike NR2 and NR3, and provides the substrate for assembly of the N-methyl-D-aspartate receptor.

Received for publication, April 2, 2007 , and in revised form, July 2, 2007.

^* 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 To whom correspondence should be addressed: Tel.: 44-1865-271-896; Fax: 44-1865-271-647; E-mail: jeff.mcilhinney{at}pharm.ox.ac.uk.

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