Antagonists of NMDA-Activated Current in Cortical Neurons: Competition with Glycine and Blockade of Open Channels

  • James E. Huettner
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 268)


There is increasing evidence that ion channels activated by L-glutamate underlie rapid excitatory synaptic transmission throughout the vertebrate central nervous system (Mayer and Westbrook, 1987) Nearly 30 years ago, glutamate was found to depolarize neurons in most areas of the brain and spinal cord (Hayashi, 1954; Curtis et al. 1960; Krnjevic and Phillis, 1963) but it was not until pharmacological experiments revealed the presence of several distinct receptors (Watkins and Olverman, 1987) for glutamate that significant progress was made toward understanding the mechanisms of glutamate excitation. Over the past ten years, the discovery of selective agonists and antagonists has played a major role in defining the subtypes of glutamate receptors (Dingledine et al. 1988) and recent studies (Jahr and Stevens, 1987; Ascher et al., 1988; Cull-Candy et al., 1988) of whole-cell and single channel currents using the patch clamp technique (Hamill et al., 1981) have begun to provide information about the channels gated by glutamate receptors.


NMDA Receptor Kynurenic Acid Excitatory Amino Acid Receptor Glycine Site Unpublished Experiment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. E. Aizenman, S. A. Lipton, and R. H. Loring, Selective modulation of NMDA responses by reduction an oxidation, Neuron 2: 1257 (1989).PubMedCrossRefGoogle Scholar
  2. N. A. Anis, S. C. Berry, N. R. Burton, and D. Lodge, The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate, Br. J. Pharmacol. 79: 565 (1983).PubMedCrossRefGoogle Scholar
  3. C. M. Armstrong, Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons, J. Gen. Physiol. 58: 413 (1971).PubMedCrossRefGoogle Scholar
  4. P. Ascher, P. Bregestovski, and L. Nowak, N-methyl-D-aspartate activated channels of mouse central neurones in magnesium-free solutions. J. Physiol. 399: 207 (1988).PubMedGoogle Scholar
  5. P. Ascher and L. Nowak, The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture, J. Physiol. 399: 247 (1988).PubMedGoogle Scholar
  6. S. G. Cull-Candy, J. R. Howe, and D. C. Ogden, Noise and single channels activated by excitatory amino acids in rat cultured cerebellar granule neurons, J. Physiol. 400: 189 (1988).PubMedGoogle Scholar
  7. D. R. Curtis, J. W. Phillis, and J. C. Watkins, The chemical excitation of spinal neurones by certain acidic amino acids, J. Physiol. 150: 656 (1960).PubMedGoogle Scholar
  8. R. Dingledine, L. M. Boland, N. L. Chamberlin, K. Kawasaki, N. W. Kleckner, S. F. Traynelis, and T. A. Verdoorn, Amino acid receptors and uptake systems in the mammalian central nervous system, CRC Crit. Rev. Neurobiol. 4: 1 (1988).Google Scholar
  9. J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, The tautomerism of heterocycles, Adv. Heterocyclic Chem. Supp. 1 (1976).Google Scholar
  10. R. H. Evans, A. A. Francis, and J. C. Watkins, Mg2+ -like selective antagonism of excitatory amino acid-induced responses by a,e-diaminopimelic acid, D-a-aminoadipate and HA-966 in isolated spinal cord of frog and immature rat, Brain Res. 148: 536 (1978).PubMedCrossRefGoogle Scholar
  11. R. H. Evans, S. J. Evans, P. C. Pook, and D. C. Sunter, 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. Pharmac. 91: 531 (1987).CrossRefGoogle Scholar
  12. E. J. Fletcher and D. Lodge, Glycine reverses antagonism of N-methyl-D-aspartate (NMDA) by 1-hydroxy-3-aminopyrrolidone (HA-966) but not by D-2-amino-5-phosphonovalerate (D-AP5) on rat cortical slices, Eur. J. Pharmacol. 151: 161 (1988).PubMedCrossRefGoogle Scholar
  13. A. C. Foster and J. A. Kemp, HA-966 antagonizes N-methyl-D-aspartate receptors through a selective interaction with the glycine modulatory site, J. Neurosci. 9: 2191 (1989).PubMedGoogle Scholar
  14. W. Haefely, E. Kyburz, M. Gerecke, and M. Mohler, Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure activity relationships of their agonists and antagonists, Adv. Drug Res. 14: 165 (1985).Google Scholar
  15. O. Hamill, A. Marty, E. Neher, B. Sakmann, and F. J. Sigworth, Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pfluegers Archiv. 391: 85 (1981).PubMedCrossRefGoogle Scholar
  16. T. Hayashi, Effects of sodium glutamate on the nervous system, Keio J. Med. 3: 183 (1954).CrossRefGoogle Scholar
  17. C. R. Honey, Z. Miljkovic, and J.F. MacDonald, Ketamine and phencyclidine cause a voltage-dependent block of responses to L-aspartic acid, Neurosci. Lett. 61: 135 (1985).PubMedCrossRefGoogle Scholar
  18. J. E. Huettner and B. P. Bean, Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels, Proc. Natl. Acad. Sci. USA 85: 1307 (1988).PubMedCrossRefGoogle Scholar
  19. J. E. Huettner, Indole-2-carboxylic acid: a competitive antagonist of potentiation by glycine at the NMDA receptor, Science 243: 1611 (1989).PubMedCrossRefGoogle Scholar
  20. J. E. Huettner and R. W. Baughman, Primary culture of identified neurons from the visual cortex of postnatal rats, J. Neurosci. 6: 3044 (1986).PubMedGoogle Scholar
  21. C. E. Jahr and C. F. Stevens, Glutamate activates multiple single channel conductances in hippocampal neurons, Nature 325: 522 (1987).PubMedCrossRefGoogle Scholar
  22. J. W. Johnson and P. Ascher, Glycine potentiates the NMDA response in cultured mouse brain neurons, Nature 325: 529 (1987).PubMedCrossRefGoogle Scholar
  23. J. A. Kemp, A. C. Foster, P. D. Leeson, T. Priestley, R. Tridgett, L. L. Iversen, and G. N. N. W. Kleckner and R. Dingledine, Requirement for glycine in activation of NMDA receptors expressed in Xenopus oocytes, Science 241: 835 (1988).CrossRefGoogle Scholar
  24. M. Kessler, T. Terramani, G. Lynch, and M. Baudry, A glycine site associated with N-methylD-aspartic acid receptors: characterization and identification of a new class of antagonists, J. Neurochem. 52: 1319 (1989).PubMedCrossRefGoogle Scholar
  25. Y. Kloog, V. Nadler, and M. Sokolovsky, Mode of binding of 13H]dibenzocycloalkenimine (MK-801) to the N-methyl-D-aspartate (NMDA) receptor and its therapeutic implication, Febs. Lett. 230: 167 (1988).PubMedCrossRefGoogle Scholar
  26. K. Krnjevic and J. W. Phillis, Iontophoretic studies of neurones in the mammalian cerebral cortex, J. Physiol. 165: 274 (1963).PubMedGoogle Scholar
  27. L. Kushner, J. Lerma, R. S. Zukin, M. V. L. Bennett, Coexpression of N-methyl-D-aspartate and phencyclidine receptors in Xenopus oocytes injected with rat brain mRNA, Proc. Nati. Acad. Sci. USA 85: 3250 (1988).CrossRefGoogle Scholar
  28. J. F. MacDonald, Z. Miljkovic, and P. Pennefather, Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine, J. Neurophysiol. 58: 251 (1987).PubMedGoogle Scholar
  29. M. L. Mayer and G. L. Westbrook, The physiology of excitatory amino acids in the vertebrate central nervous system, Prog. Neurobiol. 28: 197 (1987).PubMedCrossRefGoogle Scholar
  30. M. L. Mayer, A. B. MacDermott, G. L. Westbrook, S. J. Smith, and J. L. Barker, Agonist-and voltage-gated calcium entry in cultured mouse spinal cord neurons under voltage clamp measured with arsenazo III, J. Neurosci. 7: 3230 (1987).PubMedGoogle Scholar
  31. M. L. Mayer and G. L. Westbrook, The action of N-methyl-D-aspartic acid on mouse spinal neurones in culture, J. Physiol. 361: 65 (1985).PubMedGoogle Scholar
  32. M. L. Mayer, G. L. Westbrook, and L. Vyklicky, Jr., Sites of antagonist action on N-methyl-D-aspartic acid receptors studied using fluctuation analysis and a rapid perfusion technique. J. Neurophysiol. 60: 65 (1988)Google Scholar
  33. C. Miller, R. Latorre, and I. Reisin, Coupling of voltage-dependent gating and Ba++ block in the high-conductance, Ca++-activated K+ channel, J. Gen. Physiol. 90: 427 (1987).PubMedCrossRefGoogle Scholar
  34. E. Neher and J. H. Steinbach, Local anaesthetics transiently block currents through single acetylcholine receptor channels, J. Physiol. 277: 153 (1978).PubMedGoogle Scholar
  35. L. Nowak, P. Bregestovski, P. Ascher, A. Herbet, and A. Prochiantz, Magnesium gates gluta- mate activated channels in mouse central neurons, Nature 307: 462 (1984).PubMedCrossRefGoogle Scholar
  36. S. Peters, J. Koh, and D. W. Choi, Zinc selectively blocks the action of N-methyl-D-aspartate on cortical neurons, Science 236: 589 (1987).PubMedCrossRefGoogle Scholar
  37. E. Sernagor, D. Kuhn, L. Vyklicky, Jr., and M. L. Mayer, Open channel block of NMDA receptor responses evoked by tricyclic antidepressants, Neuron 2: 1211 (1989).CrossRefGoogle Scholar
  38. T. A. Verdoorn and R. Dingledine, Excitatory amino acid receptors expressed in Xenopus oocytes: agonist pharmacology, Mol. Pharmacol. 34: 298 (1988).PubMedGoogle Scholar
  39. J. C. Watkins and H. J. Olverman, Agonists and antagonists of excitatory amino acid receptors, Trends Neurosci. 10: 265 (1987).CrossRefGoogle Scholar
  40. G. L. Westbrook and M. L. Mayer, Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons, Nature 328: 640 (1987).PubMedCrossRefGoogle Scholar
  41. E. H. F. Wong, J. A. Kemp, T. Priestley, A. R. Knight, G. N. Woodruff, and L. L. Iversen, The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist, Proc. Natl. Acad. Sci. USA 83: 7104 (1986).PubMedCrossRefGoogle Scholar
  42. Woodruff, 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex, Proc. Natl. Acad. Sci. USA 85: 6547 (1988).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • James E. Huettner
    • 1
  1. 1.Department of NeurobiologyHarvard Medical SchoolBostonUSA

Personalised recommendations