![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
BM Baron, BL Harrison, FP Miller, IA McDonald, FG Salituro, CJ Schmidt, SM Sorensen, HS White and MG Palfreyman
Merrell Dow Research Institute, Cincinati, Ohio 45215.
5,7-Dichlorokynurenic acid (5,7-DCKA), one of the most potent excitatory amino acid receptor antagonists yet described, binds to a strychnine-insensitive glycine binding site located on the N-methyl-D- aspartate (NMDA) receptor complex (Ki = 79 nM versus [3H]glycine). 5,7- DCKA (10 microM) antagonized the ability of NMDA to stimulate the binding of the radiolabeled ion channel blocker N-[3H][1-(2- thienyl)cyclohexyl]-piperidine ([3]TCP). Glycine was able to overcome this effect and in the presence of 5,7-DCKA enhanced [3H]TCP binding to antagonist-free levels. 5,7-DCKA completely and noncompetitively antagonized several NMDA receptor-mediated biochemical and electrophysiological responses. Thus, micromolar concentrations of 5,7- DCKA inhibited NMDA-stimulated elevation of cytosolic calcium in cultured hippocampal neurons, cGMP accumulation in cerebellar slices, and norepinephrine release from hippocampal slices. The glycine antagonist could also block the action of synaptically released agonist, as shown by its ability to inhibit the increase in the magnitude of the population spike that follows tetanic stimulation of the hippocampus in vitro (long term potentiation). Inclusion of glycine or D-serine prevented all these effects of the antagonist. 5,7-DCKA was a potent anticonvulsant when administered intracerebroventricularly to mice. As in the in vitro experiments, the dose-response curve for the antagonist was shifted rightward in a parallel fashion when D-serine was coinjected. This spectrum of activity displayed by a compound acting at the glycine binding site suggests that the therapeutic utility of glycine antagonists will be similar to those proposed for other types of glutamate receptor antagonists.
This article has been cited by other articles:
|
|
 |
|
  P. E. Chen, M. T. Geballe, E. Katz, K. Erreger, M. R. Livesey, K. K. O'Toole, P. Le, C. J. Lee, J. P. Snyder, S. F. Traynelis, et al. Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes J. Physiol., January 1, 2008; 586(1): 227 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Smothers and J. J. Woodward Pharmacological Characterization of Glycine-Activated Currents in HEK 293 Cells Expressing N-Methyl-D-aspartate NR1 and NR3 Subunits J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 739 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Reigada, W. Lu, and C. H. Mitchell Glutamate acts at NMDA receptors on fresh bovine and on cultured human retinal pigment epithelial cells to trigger release of ATP J. Physiol., September 15, 2006; 575(3): 707 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Katsuki, M. Nonaka, H. Shirakawa, T. Kume, and A. Akaike Endogenous D-Serine Is Involved in Induction of Neuronal Death by N-Methyl-D-aspartate and Simulated Ischemia in Rat Cerebrocortical Slices J. Pharmacol. Exp. Ther., November 1, 2004; 311(2): 836 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yang, W. Ge, Y. Chen, Z. Zhang, W. Shen, C. Wu, M. Poo, and S. Duan Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine PNAS, December 9, 2003; 100(25): 15194 - 15199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Mothet, A. T. Parent, H. Wolosker, R. O. Brady Jr., D. J. Linden, C. D. Ferris, M. A. Rogawski, and S. H. Snyder D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor PNAS, April 25, 2000; 97(9): 4926 - 4931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Danysz and C. G. Parsons Glycine and N-Methyl-D-Aspartate Receptors: Physiological Significance and Possible Therapeutic Applications Pharmacol. Rev., December 1, 1998; 50(4): 597 - 664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Viu, A. Zapata, J. L. Capdevila, L. H. Fossom, P. Skolnick, and R. Trullas Glycine Site Antagonists and Partial Agonists Inhibit N-Methyl-D-aspartate Receptor-Mediated [3H]Arachidonic Acid Release in Cerebellar Granule Cells J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 527 - 532. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
