Role of glycine in the N-methyl-D-aspartate-mediated neuronal cytotoxicity.
Current evidence indicates that glutamate acting via the N-methyl-D-aspartate (NMDA) receptor/ion channel complex plays a major role in the neuronal degeneration associated with a variety of neurological disorders. In this report the role of glycine in NMDA neurotoxicity was examined. We demonstrate that NMDA-mediated neurotoxicity is markedly potentiated by glycine and other amino acids, e.g., D-serine. Putative glycine antagonists HA-966 and 7-chlorokynurenic acid were highly effective in preventing NMDA neurotoxicity, even in the absence of added glycine. The neuroprotective action of HA-966 and 7-chlorokynurenic acid, but not that of NMDA antagonists 3-(2-carboxypiperazine-4-yl)propylphosphonate and MK-801, could be reversed by glycine. These results indicate that glycine, operating through a strychinine-insensitive glycine site, plays a central permissive role in NMDA-mediated neurotoxicity.
Patel
J
J
Molecular Pharmacology Unit, ICI Americas Inc., Wilmington, DE 19897.
Zinkand
W C
WC
Thompson
C
C
Keith
R
R
Salama
A
A
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005998:Glycine / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D012694:Serine / Q000494:pharmacology
D003986:Dibenzocycloheptenes; D010879:Piperazines; D011760:Pyrrolidinones; D001224:Aspartic Acid; D012694:Serine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine