Whole cell and single channel analysis of the kinetics of glycine‐sensitive N‐methyl‐D‐aspartate receptor desensitization

• Published in: British journal of pharmacology Vol. 109; no. 1; pp. 213 - 221
• Main Authors: Parsons, Chris G., Zong, Xiangang, Lux, Hans D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.1993; Nature Publishing; Nature Publishing Group
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Amino Acids - pharmacology; Animals; Biological and medical sciences; Cells, Cultured; Desensitization; electrophysiology; Female; glycine; Glycine - pharmacology; Kinetics; Kynurenic Acid - analogs & derivatives; Kynurenic Acid - pharmacology; Medical sciences; Miscellaneous; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; N‐methyl‐d‐aspartate (NMDA); patch clamp; Pharmacology. Drug treatments; Pregnancy; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - drug effects; Superior Colliculi - drug effects; Superior Colliculi - metabolism; superior colliculus cultured neurones; Synapses - drug effects; Synapses - metabolism; Cell culture; Desensitization; Neuron; Excitatory aminoacid; Electrophysiology; Time response relation; Glutamate receptor; Mechanism of action; NMDA receptor; In vitro; Brain (vertebrata)
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1993.tb13556.x

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 μm 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/τ S−1) against glycine concentration had a slope of 9.5* 106 M−1 S−1. 5 Recovery from desensitization following step increases in glycine or l‐alanine concentration in the continuous presence of NMDA (200 μm) 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 μm) concentration‐dependently induced an identical form of desensitization in the presence of 1 μm glycine. 9 In contrast, the competitive NMDA antagonist (±)‐amino‐phosphonovaleric acid (APV 30 to 300 μm) concentration‐dependently antagonized and slowed the onset kinetics of NMDA responses.