Masking of the endoplasmic reticulum retention signals during assembly of the NMDA receptor.
NMDA receptors are glutamate-gated ion channels that play important roles in synaptic transmission and excitotoxicity. The functional NMDA receptor is thought to be a heterotetramer composed mainly of two NR1 and two NR2 subunits. Although it is generally accepted that only correctly assembled NMDA receptors can pass the ER quality control, the mechanism underlying this process is not well understood. Using truncated and chimeric NMDA receptor subunits expressed in heterologous cells and cortical neurons, we found that the third membrane domains (M3) of both NR1 and NR2B contain signals that cause the unassembled subunits to be retained in the ER. M3 of both NR1 and NR2B and, M4 of NR1, are necessary for masking ER retention signals found in M3. Thus, our data reveal a critical role of the membrane domains in the assembly of functional NMDA receptors.
Horak
Martin
M
Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA. horakm@nidcd.nih.gov
Chang
Kai
K
Wenthold
Robert J
RJ
D000595:Amino Acid Sequence / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D008164:Luminescent Proteins; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate