An ER retention signal explains differences in surface expression of NMDA and AMPA receptor subunits

The molecular mechanisms that control the surface expression of NMDA recept ors (NMDARs) and AMPA receptors (AMPARs) are unknown. To determine the role of the intracellular C-terminal tails of glutamate receptor subunits in th e synaptic targeting of AMPARs and NMDARs, we fused the tails of the AMPAR subunits, GluR1 and GluR2, and the NMDAR subunit, NR1, to the human T lymph ocyte membrane protein CD8 and expressed these constructs in HEK293 cells a nd cultured hippocampal neurons. The GluR1 and GluR2 fusion proteins exhibi ted robust surface expression in the plasma membrane of neurons at synapses as did CD8 alone. In contrast, the NR1 fusion protein was retained intrace llularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette. This ER retention signal was overridde n either by the addition of a PDZ domain-binding motif or by mimicking phos phorylation at a site adjacent to the retention signal. These results provi de further evidence that the intracellular trafficking of AMPAR and NMDAR s ubunits are regulated independently at least in part because of differences in the protein-protein interactions of their intracellular C-terminal tail s. (C) 2001 Published by Elsevier Science Ltd.