The Glycine Coagonist Site of the NMDA Receptor

  • Raymond Dingledine
  • Nancy W. Kleckner
  • Christopher J. McBain
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 268)


The discovery of the glycine binding site on the NMDA receptor (Johnson and Ascher, 1987) is recognized as a highly significant event by those interested in receptor-channel mechanisms. It also offers a new target site in drug development for the treatment of neuropa-thologies associated with NMDA receptor activation. The list of neural dysfunctions mediated in part by. synaptic activation of NMDA receptors very likely includes epileptiform seizures (Croucher et al., 1982) and brain damage induced by ischemia or hypoxia in some models (Simon et al., 1984). Growing evidence indicates however that NMDA receptor activation is important also for establishing certain neuronal connections during development (Tsumoto et al., 1987; Kleinschmidt et al., 1987; Lincoln et al., 1988) and has been implicated in some types of learning or memory (Morris et al., 1986). Thus both agonists and antagonists of the NMDA receptor may find clinical utility in the future. Currently available NMDA receptor blockers, acting either at the glutamate binding site or the open ion channel, either have difficulty penetrating the blood-brain barrier or have unacceptable side effects such as psychosis. The glycine site appears to present a pharmacology sufficiently different from that of the other binding sites on the NMDA receptor to offer a novel target for new drug discovery.


NMDA Receptor Kynurenic Acid NMDA Receptor Activation Excitatory Amino Acid Receptor Glycine Site 
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. Barnard, E.A., M.G. Darlison and P. Seeburg. Molecular biology of the GABA-A receptor: the receptor/channel superfamily. Trends in Neurosci., 10, 502–509, (1987).CrossRefGoogle Scholar
  2. Birch, P. J., C. J. Grossman, and A. G. Hayes. 6,7-Dinitro-quinoxaline-2,3-dion and6-nitro,7cyano-quinoxaline-2,3-dion antagonise responses to NMDA in the rat spinal cord via an action at the strychnine-insensitive glycine receptor. Eur. J. Pharmacol. 6, 177–180 (1988).CrossRefGoogle Scholar
  3. Bonhaus, D.W., B.C. Burge and J.O. McNamara. Biochemical evidence that glycine allosterically regulates an NMDA receptor-coupled ion channel. Eur. J. Pharmacol., 142, 489–490, (1987).PubMedCrossRefGoogle Scholar
  4. Clarke, D.D., A.L. Lajthe and H.S. Maker. Intermediary metabolism. in G. Siegel, B. Agranoff, R.W. Albers and P. Molinoff (eds.). Basic Neurochemistry, 4th ed. Raven Press, New York, (1989).Google Scholar
  5. Croucher, M.J., J.F. Collins, and B.S. Meldrum. Anticonvulsant action of excitatory amino acid antagonists. Science 216, 899–901, 1982.PubMedCrossRefGoogle Scholar
  6. Fletcher, E. J., and D. Lodge. Glycine reverses antagonism of N-methyl-D-aspartate (NMDA) by 1-hydroxy-aminopyrrolidone-2(HA-966) but not by D-2-amino-5-phosphono-valerate (D-APV) on rat cortical slices. Eur. J. Pharmacol. 1, 161–162 (1988).Google Scholar
  7. Foster, A. C., and J. A. Kemp. HA-966 antagonizes N-methyl-D-aspartate receptors through a selective interaction with the glycine modulatory site. J.Neurochem. in press, 1989.Google Scholar
  8. Honore, T. G., S. N. Davies, J. Drejer, E. J. Fletcher, P. Jacobsen, D. Lodge, and F. E. Nielsen. Quinoxalinediones: Potent competitive non-NMDA glutamate receptor antagonists. Science 241, 701–703 (1988).PubMedCrossRefGoogle Scholar
  9. Johnson, J. W. and P. Ascher. Glycine potentiates the NMDA response in cultured mouse brain neurons, Nature 325, 529–531 (1987).PubMedCrossRefGoogle Scholar
  10. Kemp, J.A., A.C. Foster, P.D. Leeson, T. Priestly, R. Tridgett, L.L. Iversen, and G.N. 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, 6547–6550 (1988).PubMedCrossRefGoogle Scholar
  11. Kessler, M. 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, 1319–1328 (1989).PubMedCrossRefGoogle Scholar
  12. Kleckner, N. W., and R. Dingledine. Requirement for glycine in activation of N-methyl-D-aspartate receptors expressed in Xenopus oocytes, Science 241, 835–837 (1988).PubMedCrossRefGoogle Scholar
  13. Kleckner, N. W., and R. Dingledine. Selectivity of quinoxalines and kynurenines as antagonists of the glycine site on N-methyl-D-aspartate receptors. Mol. Pharmacol. in press.Google Scholar
  14. Kleinschmidt, A., M.F. Bear and W. Singer. Blockade of NMDA receptors disrupts experience -dependent plasticity of kitten striate cortex. Science 238, 355–358 (1987).PubMedCrossRefGoogle Scholar
  15. Lima-Landman, M.T. and E.X. Albuquerque. The novel neurotoxin H12-histrionicotoxin blocks the N-methyl-D-aspartate (NMDA) receptor of cultured hippocampus of the rat. Soc. Neurosci. Abst. 14, 96, 1988.Google Scholar
  16. Lincoln, J., R. Coopersmith, E. W. Harris, C. W. Cotman, and M. Leon. NMDA receptor activation and early olfactory learning. Des. Brain Res. 39, 309–312 (1988).CrossRefGoogle Scholar
  17. McBain, C. J., N. W. Kleckner, and R. Dingledine. Structural requirements for activation of the glycine coagonist site of NMDA receptors expressed in Xenopus oocytes. Mol. Pharmacol. in press.Google Scholar
  18. McNamara, D. and R. Dingledine. Requirement for glycine in NMDA-induced excitotoxicity in rat cortical cultures Soc. Neurosci. Abst. vol., in press, 1989.Google Scholar
  19. Mayer, M.L., L. Vyklicky and J. Clements. Regulation of NMDA receptor desensitization in mouse hippocampal neurons by glycine. Nature. 338, 425–427, (1989)PubMedCrossRefGoogle Scholar
  20. Morris, R.G.M., E. Anderson, G.S. Lynch and M. Baudry. Selective impariment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776, 1986.PubMedCrossRefGoogle Scholar
  21. Ransom, R. W., and N. L. Deschenes. NMDA-induced hippocampal [3H]norepinephrine release is modulated by glycine. Eur. J. Pharmacol. 6, 149–5 (1988).CrossRefGoogle Scholar
  22. Simon, R.P., J.H. Swan, T. Griffiths and B.S. Meldrum. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 226, 850–852, 1984.PubMedCrossRefGoogle Scholar
  23. Snell, L.D., R.S. Morter, and K.M. Johnson. Structural requirements for activation of the glycine receptor that modulates the N-methyl-D-aspartate operated ion channel. Eur. J. Pharmacol. 6, 105–110 (1988).Google Scholar
  24. Tsumoto, T., K. Hagihara, H. Sato, and Y. Hata. NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats. Nature 327, 513–514 (1987).PubMedCrossRefGoogle Scholar
  25. Verdoorn, T.A. and R. Dingledine. Excitatory amino acid receptors expressed in Xenopus oocytes: agonist pharmacology. Molec. Pharmacol., 34, 298–307, 1988.Google Scholar
  26. Verdoorn, T.A., N.W. Kleckner, and R. Dingledine. Rat brain N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Science 238, 1114–1116 (1987).PubMedCrossRefGoogle Scholar
  27. Verdoorn, T. A., N.W. Kleckner, and R. Dingledine. N-methyl-D-aspartate/glycine and quisqualate/kainate receptors expressed in Xenopus oocytes: Antagonist pharmacology. Mol. Pharmacol. 35, 360–368 (1989).Google Scholar
  28. Watkins, J.C. and H.J. Olverman. Agonists and antagonists for excitatory amino acid receptors. Trends in Neurosci., 10, 265–272, 1987.CrossRefGoogle Scholar
  29. Watson, G.B., W.F. Hood, J.B. Monahan, and T.H. Lanthorn. Kynurenate antagonizes actions of N-methyl-D-aspartate through a glycine-sensitive receptor. Neurosci. Res. Comm. 2, 169–174 (1988).Google Scholar
  30. Wong, E.H.F., A.R. Knight, and R. Ransom. Glycine modulates [3H]MK-801 binding to the NMDA receptor in rat brain. Eur. J. Pharmacol. 142, 487–488 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • Raymond Dingledine
    • 1
  • Nancy W. Kleckner
    • 1
  • Christopher J. McBain
    • 1
  1. 1.Department of PharmacologyUniversity of North Carolina School of MedicineChapel HillUSA

Personalised recommendations