Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors

Functional NMDA receptors are heteromultimeric complexes of the NR1 subunit in combination with at least one of the four NR2 subunits (A-D). Coexpress ion of NR3A, an additional subunit of the NMDA receptor family, modifies NM DA-mediated responses. It is unclear whether NR3A interacts directly with N R1 and/or NR2 subunits and how such association might regulate the intracel lular trafficking and membrane expression of NR3A. Here we show that NR3A c oassembles with NR1-1a and NR2A to form a receptor complex with distinct si ngle-channel properties and a reduced relative calcium permeability. NR3A a ssociates independently with both NR1-1a and NR2A in the endoplasmic reticu lum, but only heteromeric complexes containing the NR1-1a NMDA receptor sub unit are targeted to the plasma membrane. Homomeric NR3A complexes or compl exes composed of NR2A and NR3A were not detected on the cell surface and ar e retained in the endoplasmic reticulum. Coexpression of NR1-1a facilitates the surface expression of NR3A-containing receptors, reduces the accumulat ion of NR3A subunits in the endoplasmic reticulum, and induces the appearan ce of intracellular clusters where both subunits are colocalized. Our data demonstrate a role for subunit oligomerization and specifically assembly wi th the NR1 subunit in the trafficking and plasma membrane targeting of the receptor complex.