Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1988 Sep;85(17):6547–6550. doi: 10.1073/pnas.85.17.6547

7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex.

J A Kemp 1, A C Foster 1, P D Leeson 1, T Priestley 1, R Tridgett 1, L L Iversen 1, G N Woodruff 1
PMCID: PMC282010  PMID: 2842779

Abstract

Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical slices 7-Cl KYNA (10-100 microM) noncompetitively inhibited N-Me-D-Asp responses, and this effect could be reversed by the addition of glycine (100 microM) or D-serine (100 microM). Radioligand binding experiments showed that 7-Cl KYNA had a much higher affinity for the strychnine-insensitive [3H]glycine binding site (IC50 = 0.56 microM) than for the N-Me-D-Asp (IC50 169 microM), quisqualate (IC50 = 153 microM), or kainate (IC50 greater than 1000 microM) recognition sites. In whole-cell patch-clamp recordings from rat cortical neurones in culture, the inhibitory effects of 7-Cl KYNA on N-Me-D-Asp-induced currents could not be overcome by increasing the N-Me-D-Asp concentration but could be reversed by increasing the glycine concentration. 7-Cl KYNA could completely abolish N-Me-D-Asp responses, including basal responses in the absence of added glycine, suggesting that it may possess negative modulatory effects at the glycine site. These findings indicate that the glycine modulatory site is functional in intact adult tissue and that 7-Cl KYNA should prove to be a selective tool for elucidating the involvement of this site in physiological and pathological events mediated by N-Me-D-Asp receptors.

Full text

PDF
6547

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bonhaus D. W., Burge B. C., McNamara J. O. Biochemical evidence that glycine allosterically regulates an NMDA receptor-coupled ion channel. Eur J Pharmacol. 1987 Oct 27;142(3):489–490. doi: 10.1016/0014-2999(87)90096-3. [DOI] [PubMed] [Google Scholar]
  2. Braestrup C., Schmiechen R., Neef G., Nielsen M., Petersen E. N. Interaction of convulsive ligands with benzodiazepine receptors. Science. 1982 Jun 11;216(4551):1241–1243. doi: 10.1126/science.6281892. [DOI] [PubMed] [Google Scholar]
  3. Bristow D. R., Bowery N. G., Woodruff G. N. Light microscopic autoradiographic localisation of [3H]glycine and [3H]strychnine binding sites in rat brain. Eur J Pharmacol. 1986 Jul 31;126(3):303–307. doi: 10.1016/0014-2999(86)90062-2. [DOI] [PubMed] [Google Scholar]
  4. Davies J., Evans R. H., Herrling P. L., Jones A. W., Olverman H. J., Pook P., Watkins J. C. CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]D-AP5 binding sites on brain membranes and anticonvulsant activity. Brain Res. 1986 Sep 10;382(1):169–173. doi: 10.1016/0006-8993(86)90127-7. [DOI] [PubMed] [Google Scholar]
  5. Evans R. H., Evans S. J., Pook P. C., Sunter D. C. A comparison of excitatory amino acid antagonists acting at primary afferent C fibres and motoneurones of the isolated spinal cord of the rat. Br J Pharmacol. 1987 Jul;91(3):531–537. doi: 10.1111/j.1476-5381.1987.tb11246.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Foster A. C., Fagg G. E. Comparison of L-[3H]glutamate, D-[3H]aspartate, DL-[3H]AP5 and [3H]NMDA as ligands for NMDA receptors in crude postsynaptic densities from rat brain. Eur J Pharmacol. 1987 Jan 20;133(3):291–300. doi: 10.1016/0014-2999(87)90025-2. [DOI] [PubMed] [Google Scholar]
  7. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  8. Honoré T., Nielsen M. Complex structure of quisqualate-sensitive glutamate receptors in rat cortex. Neurosci Lett. 1985 Feb 28;54(1):27–32. doi: 10.1016/s0304-3940(85)80113-0. [DOI] [PubMed] [Google Scholar]
  9. Johnson J. W., Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 1987 Feb 5;325(6104):529–531. doi: 10.1038/325529a0. [DOI] [PubMed] [Google Scholar]
  10. Kaplan F. S., Brighton C. T., Boytim M. J., Selzer M. E., Lee V., Spindler K., Silberberg D., Black J. Enhanced survival of rat neonatal cerebral cortical neurons at subatmospheric oxygen tensions in vitro. Brain Res. 1986 Oct 1;384(1):199–203. doi: 10.1016/0006-8993(86)91240-0. [DOI] [PubMed] [Google Scholar]
  11. Kemp J. A., Marshall G. R., Wong E. H., Woodruff G. N. The affinities, potencies and efficacies of some benzodiazepine-receptor agonists, antagonists and inverse-agonists at rat hippocampal GABAA-receptors. Br J Pharmacol. 1987 Jul;91(3):601–608. doi: 10.1111/j.1476-5381.1987.tb11253.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kishimoto H., Simon J. R., Aprison M. H. Determination of the equilibrium dissociation constants and number of glycine binding sites in several areas of the rat central nervous system, using a sodium-independent system. J Neurochem. 1981 Oct;37(4):1015–1024. doi: 10.1111/j.1471-4159.1981.tb04489.x. [DOI] [PubMed] [Google Scholar]
  13. Perkins M. N., Stone T. W. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982 Sep 9;247(1):184–187. doi: 10.1016/0006-8993(82)91048-4. [DOI] [PubMed] [Google Scholar]
  14. Polc P., Bonetti E. P., Schaffner R., Haefely W. A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone. Naunyn Schmiedebergs Arch Pharmacol. 1982 Dec;321(4):260–264. doi: 10.1007/BF00498510. [DOI] [PubMed] [Google Scholar]
  15. Reynolds I. J., Murphy S. N., Miller R. J. 3H-labeled MK-801 binding to the excitatory amino acid receptor complex from rat brain is enhanced by glycine. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7744–7748. doi: 10.1073/pnas.84.21.7744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Simon J. R., Contrera J. F., Kuhar M. J. Binding of [3H] kainic acid, and analogue of Lglutamate, to brain membranes. J Neurochem. 1976 Jan;26(1):141–147. [PubMed] [Google Scholar]
  17. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Wong E. H., Knight A. R., Ransom R. Glycine modulates [3H]MK-801 binding to the NMDA receptor in rat brain. Eur J Pharmacol. 1987 Oct 27;142(3):487–488. doi: 10.1016/0014-2999(87)90095-1. [DOI] [PubMed] [Google Scholar]
  19. Yazulla S., Cunningham J., Neal M. Stimulated release of endogenous GABA and glycine from the goldfish retina. Brain Res. 1985 Oct 21;345(2):384–388. doi: 10.1016/0006-8993(85)91022-4. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES