A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux.
Tyrosine phosphorylation can upregulate NMDA receptor activity during pathological and physiological alterations of synaptic strength. Here we describe downregulation of recombinant NR1/2A receptors by tyrosine dephosphorylation that requires agonist binding, but is independent of ion flux. The tyrosine residues involved in this new form of NMDA receptor modulation likely form a 'ring' adjacent to the last transmembrane domain. The downregulation was due to a reduction in the number of functional channels, and was blocked by co-expressing a dominant-negative mu2-subunit of the clathrin-adaptor protein AP-2. Our results provide a mechanism by which synaptic NMDA receptors can be modulated in a use-dependent manner even when the postsynaptic membrane is not sufficiently depolarized to relieve channel block by magnesium ions.
Vissel
B
B
The Vollum Institute, OHSU-L474, 3181 SW Sam Jackson Park Rd., Portland, Oregon 97201, USA.
Krupp
J J
JJ
Heinemann
S F
SF
Westbrook
G L
GL
D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D033983:Adaptor Protein Complex mu Subunits; D033942:Adaptor Proteins, Vesicular Transport; D001640:Bicuculline / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D003001:Cloning, Molecular; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015536:Down-Regulation; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism*; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation
C499064:AP1M2 protein, human; C510070:AP3M2 protein, human; D033961:Adaptor Protein Complex 1; D033962:Adaptor Protein Complex 2; D033963:Adaptor Protein Complex 3; D033983:Adaptor Protein Complex mu Subunits; D033942:Adaptor Proteins, Vesicular Transport; D015704:CD4 Antigens; D004791:Enzyme Inhibitors; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C499065:adaptor protein complex 1, mu 2 subunit; C438886:adaptor protein complex 2, mu 2 subunit; D019000:Phosphotyrosine; D013779:Tetrodotoxin; D004533:Egtazic Acid; D016291:Dizocilpine Maleate; D008274:Magnesium; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; D001640:Bicuculline