Effects of (+)-HA-966 and 7-chlorokynurenic acid on the kinetics of N- methyl-D-aspartate receptor agonist responses in rat cultured cortical neurons

JA Kemp and T Priestley

Merck, Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.

It has been suggested that one of the effects of glycine at the N- methyl-D-aspartate (NMDA) receptor complex is to reduce the amount of apparent receptor desensitization. Thus, blockade with a glycine site antagonist results in NMDA responses that show an increased amount of fade. In agreement with this, we found that antagonism of NMDA-evoked whole-cell currents by 7-chlorokynurenic acid (7-Cl-KYNA) indeed resulted in NMDA responses that displayed an increased amount of fade. However, those responses that were antagonized by (+)-HA-966 showed the opposite, i.e., less tendency to fade. On examination of these responses, it appeared that those produced in the presence of (+)-HA- 966 were slower in onset and faster in offset than control responses recorded in the presence of glycine alone. Kinetic analysis of the on- and off-rates of NMDA- and glutamate-evoked NMDA receptor-mediated responses revealed that these were markedly affected by (+)-HA-966 but only slightly by 7-Cl-KYNA. The decrease of the glutamate response decay time constant and the increase of the response rise time constant produced by (+)-HA-966 indicated that it reduced the affinity of glutamate for its recognition site on the NMDA receptor by 5-fold. These results suggest that binding of (+)-HA-966 to the glycine site on the NMDA receptor complex produces an allosteric reduction in the affinity of agonists for the glutamate recognition site, whereas 7-Cl- KYNA has relatively little effect and, thus, acts more as a pure antagonist at the glycine site.

Volume 39, Issue 5, pp. 666-670, 05/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics

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]

				A. I. Sobolevsky, M. V. Yelshansky, and B. I. Khodorov Eosine-Induced Blockade of N-Methyl-D-aspartate Channels in Acutely Isolated Rat Hippocampal Neurons Mol. Pharmacol., February 1, 2000; 57(2): 334 - 341. [Abstract] [Full Text]

				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]

				C. G. Parsons, W. Danysz, G. Quack, S. Hartmann, B. Lorenz, C. Wollenburg, L. Baran, E. Przegalinski, W. Kostowski, P. Krzascik, et al. Novel Systemically Active Antagonists of the Glycine Site of the N-Methyl-D-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1264 - 1275. [Abstract] [Full Text]