Oxygen free radicals regulate NMDA receptor function via a redox modulatory site

Neuron. 1990 Dec;5(6):841-6. doi: 10.1016/0896-6273(90)90343-e.


A novel modulatory site on the N-methyl-D-aspartate (NMDA) receptor that is sensitive to sulfhydryl redox reagents was recently described. Here we report that this redox modulatory site is susceptible to oxidation by reactive oxygen species endogenous to the CNS. Oxygen free radicals generated by xanthine and xanthine oxidase were observed to decrease NMDA-induced changes in intracellular free Ca2+ concentrations and NMDA-evoked cation currents in cortical neurons in culture. Additionally, a sublethal production of free radicals by xanthine and xanthine oxidase reversed a dithiothreitol-induced enhancement of NMDA-mediated neurotoxicity in vitro. These results show that NMDA receptor function is modulated at its redox site by endogenous substances that normally accompany tissue reperfusion following an ischemic event. This novel mechanism for NMDA receptor regulation may have profound implications in the outcome of glutamate neurotoxicity in vivo.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Calcium / metabolism
  • Catalase / pharmacology
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / embryology
  • Cerebral Cortex / physiology*
  • Dithiothreitol / pharmacology
  • Electric Conductivity
  • Free Radicals
  • Glycine / pharmacology
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Oxidation-Reduction
  • Oxygen / pharmacology*
  • Rats
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Superoxide Dismutase / pharmacology
  • Xanthine
  • Xanthine Oxidase / metabolism
  • Xanthines / metabolism


  • Free Radicals
  • Receptors, N-Methyl-D-Aspartate
  • Xanthines
  • Xanthine
  • N-Methylaspartate
  • Catalase
  • Superoxide Dismutase
  • Xanthine Oxidase
  • Oxygen
  • Calcium
  • Dithiothreitol
  • Glycine