REGULATED SUBCELLULAR-DISTRIBUTION OF THE NR1 SUBUNIT OF THE NMDA RECEPTOR

NMDA (N-methyl-D-aspartate) receptors are selectively localized at the postsynaptic membrane of excitatory synapses in the mammalian brain. The molecular mechanisms underlying this localization were investigate d by expressing the NR1 subunit of the NMDA receptor in fibroblasts. N R1 splice variants containing the first COOH-terminal exon cassette (N R1A and NR1D) were located in discrete, receptor-rich domains associat ed with the plasma membrane. NR1 splice variants lacking this exon cas sette (NR1C and NR1E) were distributed throughout the cell, with large amounts of NR1 protein present in the cell interior. Insertion of thi s exon cassette into the COOH-terminus of the GluR1 AMPA (alpha-amino- 3-hydroxy-5-methyl-4-isoxazole propionate) receptor was sufficient to cause GluR1 to be localized to discrete, receptor-rich domains. Furthe rmore, protein kinase C phosphorylation of specific serines within thi s exon disrupted the receptor-rich domains. These results demonstrate that amino acid sequences contained within the NR1 molecule serve to l ocalize this receptor subunit to discrete membrane domains in a manner that is regulated by alternative splicing and protein phosphorylation .