Whole cell and single channel analysis of the kinetics of glycine-sensitive N-methyl-D-aspartate receptor desensitization.
1. The kinetics of glycine-sensitive, N-methyl-D-aspartate (NMDA) receptor desensitization were investigated in cultured neurones with the patch clamp technique. 2. The degree of fast NMDA-receptor desensitization was inversely related to glycine concentration. Thus, increasing concentrations of glycine from 30 nM to 2.5 microM potentiated desensitized NMDA responses (873% +/- 101%) to a greater degree than peak responses (260% +/- 27%). 3. The desensitization was due to a decrease in the affinity of glycine for the strychnine-insensitive, glycine modulatory site (glycineB site) following activation of the NMDA-receptor complex. Thus, the A50 for glycine in potentiating peak responses (77 nM, 95% confidence limited 58-104 nM) was five fold lower than that for plateau responses (399 nM, 340-468 nM). 4. The rate of desensitization was related to glycine concentration such that a reciprocal plot of desensitization rate (1/tau S-1) against glycine concentration had a slope of 9.5* 10(6) M-1 S-1. 5. Recovery from desensitization following step increases in glycine or L-alanine concentration in the continuous presence of NMDA (200 microM) reflected the association kinetics of the glycineB agonist used. 6. The rate and degree of NMDA receptor desensitization was independent of holding potential. 7. NMDA receptor desensitization was also evident at the single channel level. 8. The glycineB antagonist 7-chlorokynurenic acid (7-Chl-Kyn 3 and 10 microM) concentration-dependently induced an identical form of desensitization in the presence of 1 microM glycine. 9. In contrast, the competitive NMDA antagonist (+/-)-amino-phosphonovaleric acid (APV 30 to 300 microM) concentration-dependently antagonized and slowed the onset kinetics of NMDA responses.
Parsons
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CG
Department of Neurophysiology, Max-Planck Institute for Psychiatry, Planegg-Martinsried, Germany.
Zong
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Lux
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HD
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005998:Glycine / Q000494:pharmacology*; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013477:Superior Colliculi / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
D000596:Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D005998:Glycine