PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants

The NMDA receptor NR1 subunit has four splice variants that differ in their C-terminal, cytoplasmic domain. We investigated the contribution of the C- terminal cassettes, CO, C1, C2, and C2', to trafficking of NR1 in heterolog ous cells and neurons. We identified an ER retention signal (RRR) in the C1 cassette of NR1, which is similar to the RXR motif in ATP-sensitive K+ cha nnels (Zerangue et al., 1999). We found that surface expression of NR1-3, w hich contains C1, is due to a site on the C2' cassette, which includes the terminal 4 amino acid PDZ-interacting domain. This site suppresses ER reten tion of the C1 cassette and leads to surface expression. These findings sug gest a role for PDZ proteins in facilitating the transition of receptors fr om an intracellular pool to the surface of the neuron.