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The Journal of Neuroscience, February 15, 2001, 21(4):1228-1237

Assembly with the NR1 Subunit Is Required for Surface Expression of NR3A-Containing NMDA Receptors

Isabel Pérez-Otaño¹, Christine T. Schulteis¹, Anis Contractor¹, Stuart A. Lipton², James S. Trimmer³, Nikolaus J. Sucher⁴, and Stephen F. Heinemann¹

¹ Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, ² Center for Neuroscience and Aging, The Burnham Institute, La Jolla, California 92037, ³ Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794, and ⁴ Department of Biology, Hong Kong University of Science and Technology, Hong Kong, China

Functional NMDA receptors are heteromultimeric complexes of the NR1 subunit in combination with at least one of the four NR2 subunits (A-D). Coexpression of NR3A, an additional subunit of the NMDA receptor family, modifies NMDA-mediated responses. It is unclear whether NR3A interacts directly with NR1 and/or NR2 subunits and how such association might regulate the intracellular trafficking and membrane expression of NR3A. Here we show that NR3A coassembles with NR1-1a and NR2A to form a receptor complex with distinct single-channel properties and a reduced relative calcium permeability. NR3A associates independently with both NR1-1a and NR2A in the endoplasmic reticulum, but only heteromeric complexes containing the NR1-1a NMDA receptor subunit are targeted to the plasma membrane. Homomeric NR3A complexes or complexes composed of NR2A and NR3A were not detected on the cell surface and are retained in the endoplasmic reticulum. Coexpression of NR1-1a facilitates the surface expression of NR3A-containing receptors, reduces the accumulation of NR3A subunits in the endoplasmic reticulum, and induces the appearance of intracellular clusters where both subunits are colocalized. Our data demonstrate a role for subunit oligomerization and specifically assembly with the NR1 subunit in the trafficking and plasma membrane targeting of the receptor complex.

Key words: NMDA receptor; glutamate; calcium permeability; single channel; surface expression; assembly; NR3A

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2141228-10$05.00/0

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