title: A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux.
abstract: 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.
authors.affiliation: The Vollum Institute, OHSU-L474, 3181 SW Sam Jackson Park Rd., Portland, Oregon 97201, USA.
authors.forename: B
authors.initials: B
authors.lastname: Vissel
authors.forename: J J
authors.initials: JJ
authors.lastname: Krupp
authors.forename: S F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: G L
authors.initials: GL
authors.lastname: Westbrook
mesh_terms: 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
chemical_list: 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