Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking.
Modification of NMDA receptor function and trafficking contributes to the regulation of synaptic transmission and is important for several forms of synaptic plasticity. Here, we report that NMDA receptor subunits NR2A and NR2B have two distinct clusters of palmitoylation sites in their C-terminal region. Palmitoylation within the first cluster on a membrane-proximal region increases tyrosine phosphorylation of tyrosine-based internalization motifs by Src family protein tyrosine kinases, leading to enhanced stable surface expression of NMDA receptors. In addition, palmitoylation of these sites regulates constitutive internalization of the NMDA receptor in developing neurons. In marked contrast, palmitoylation of the second cluster in the middle of C terminus by distinct palmitoyl transferases causes receptors to accumulate in the Golgi apparatus and reduces receptor surface expression. These data suggest that regulated palmitoylation of NR2 subunits differentially modulates receptor trafficking and might be important for NMDA-receptor-dependent synaptic plasticity.
Hayashi
Takashi
T
Howard Hughes Medical Institute, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Thomas
Gareth M
GM
Huganir
Richard L
RL
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D054878:Lipoylation / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010168:Palmitates / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D000779:Anesthetics, Local; C465718:GODZ protein, mouse; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010168:Palmitates; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D049452:Green Fluorescent Proteins; D014443:Tyrosine; D013779:Tetrodotoxin; D011505:Protein-Tyrosine Kinases; D003545:Cysteine