A use-dependent tyrosine dephosphorylation of NMDA receptors is independent of ion flux

Nat Neurosci. 2001 Jun;4(6):587-96. doi: 10.1038/88404.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Protein Complex 1*
  • Adaptor Protein Complex 2*
  • Adaptor Protein Complex 3*
  • Adaptor Protein Complex mu Subunits*
  • Adaptor Proteins, Vesicular Transport
  • Bicuculline / pharmacology
  • CD4 Antigens / genetics
  • CD4 Antigens / physiology
  • Calcium / physiology
  • Cell Line
  • Cell Membrane / physiology
  • Cloning, Molecular
  • Dizocilpine Maleate / pharmacology
  • Down-Regulation
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Magnesium / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Patch-Clamp Techniques
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphotyrosine / metabolism*
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / metabolism
  • Synapses / physiology*
  • Tetrodotoxin / pharmacology
  • Transfection
  • Up-Regulation

Substances

  • AP1M2 protein, human
  • AP3M2 protein, human
  • Adaptor Protein Complex 1
  • Adaptor Protein Complex 2
  • Adaptor Protein Complex 3
  • Adaptor Protein Complex mu Subunits
  • Adaptor Proteins, Vesicular Transport
  • CD4 Antigens
  • Enzyme Inhibitors
  • NR1 NMDA receptor
  • NR2A NMDA receptor
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • adaptor protein complex 1, mu 2 subunit
  • adaptor protein complex 2, mu 2 subunit
  • Phosphotyrosine
  • Tetrodotoxin
  • Egtazic Acid
  • Dizocilpine Maleate
  • Magnesium
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Calcium
  • Bicuculline