NMDA receptor antagonists that bind to the strychnine-insensitive glycine site and inhibit NMDA-induced Ca2+ fluxes and [3H]GABA release

Ian J. Reynolds, Katherine M. Harris, Richard J. Miller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

We have examined the actions of putative antagonists of the strychnine-insensitive glycine-mediated modulation of the N-methyl-D-aspartate (NMDA) receptor using [3H]MK801 binding, Ca2+ influx and [3H]GABA release assays. Kynurenic acid and HA-966 inhibited [3H]MK801 binding, NMDA and glycine induced Ca2+ influx measured using fura-2 and NMDA and glycine simulated [3H]GABA release. The effects of kynurenic acid could be partially overcome by the addition of excess glutamate and glycine, indicating limited selectivity for the glycine binding site. In addition, a component of the action of kynurenic acid was insensitive to agonist concentration, indicating a third action of kynurenic acid at high concentrations. In contrast, HA-966 was 100-foled selective for the glycine compared to the NMDA site. HA-966 only partially inhibited [3H]MK801 binding (IC50 19.7 μM), NMDA-induced Ca2+ influx and neurotransmitter release. The failure of HA-966 to completely block NMDA responses, even at high concentrations, suggests that glycine may not be an absolute requirement for the activation of NMDA receptors under these experimental conditions.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalEuropean Journal of Pharmacology: Molecular Pharmacology
Volume172
Issue number1
DOIs
StatePublished - Mar 7 1989

Keywords

  • Ca (intracllular)
  • GABA release
  • HA-966
  • Kynurenic acid
  • MK801
  • NMDA receptors

ASJC Scopus subject areas

  • Pharmacology

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