An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing

Formation of mature excitatory synapses requires the assembly and delivery of NMDA receptors to the neuronal plasma membrane. A key step in the traffi cking of NMDA receptors to synapses is the exit of newly assembled receptor s from the endoplasmic reticulum (ER). Here we report the identification of an RXR-type ER retention/retrieval motif in the C-terminal tail of the NMD A receptor subunit NR1 that regulates receptor surface expression in hetero logous cells and in neurons. In addition, we show that PKC phosphorylation and an alternatively spliced consensus type I PDZ-binding domain suppress E R retention. These results demonstrate a novel quality control function for alternatively spliced C-terminal domains of NR1 and implicate both phospho rylation and potential PDZ-mediated interactions in the trafficking of NMDA receptors through early stages of the secretory pathway.