Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures.
Glutamate neurotoxicity was examined in cultured cerebellar granule neurons following both prolonged (20-24 h) and brief (45 min) exposure to compounds acting at strychnine-insensitive glycine receptors. Glutamate neurotoxicity was reduced in a concentration-dependent fashion by brief exposure to the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) and the competitive antagonist, 7-chlorokynurenic acid (7-CK) with a rank order efficacy: 7-CK > HA-966 > ACPC. Neither D-cycloserine (D-CS) nor glycine affected neurotoxicity produced by maximum glutamate concentrations, while glycine but not D-CS augmented the effects of submaximum glutamate concentrations. Prolonged exposure of cultures to either full (glycine) or partial agonists (ACPC, D-CS, HA-966) abolished the neuroprotective effects of ACPC and significantly diminished the neuroprotective effects of HA-966. In contrast, the neuroprotective effects of 7-CK were only marginally reduced by prolonged exposure to glycinergic ligands, while the neuroprotection afforded by compounds acting at other loci on the NMDA receptor complex (e.g. 2-amino-5-phosphonopentanoate (APV) and dizocilpine (MK-801)) were unaltered. These effects may represent homologous desensitization of the NMDA receptor complex at its strychnine-insensitive glycine receptor induced by prolonged exposure to glycinergic agonists and partial agonists. Nonetheless, levels of the NMDA receptor subunit zeta 1 mRNA were unaffected by prolonged exposure to ACPC, indicating the apparent desensitization could involve a post-translational modification of the NMDA receptor complex.
Boje
K M
KM
Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Wong
G
G
Skolnick
P
P
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D005998:Glycine / Q000502:physiology; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology; D013997:Time Factors
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D005971:Glutamates; D009498:Neurotoxins; D009838:Oligodeoxyribonucleotides; D011760:Pyrrolidinones; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C023863:1-aminocyclopropane-1-carboxylic acid; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; D013331:Strychnine; C057013:7-chlorokynurenic acid; D005998:Glycine