Noncompetitive Inhibition of N‐Methyl‐D‐Aspartate by Conantokin‐G: Evidence for an Allosteric Interaction at Polyamine Sites

Phil Skolnick, Kathleen Boje, Rachel Miller, Micheal Pennington, Maria‐Luisa ‐L Maccecchini

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Abstract: Conantokins T and G are polypeptide toxins present in snails of the genus Conus. These substances were recently reported to act as N‐methyl‐D‐aspartate (NMDA) antagonists. In the present study, we examined the possible mechanisms producing this antagonism. Conantokin‐G inhibited spermine‐ and spermidine‐stimulated [3H]MK‐801 binding to extensively washed rat forebrain membranes in a noncompetitive manner with IC50 values of ∼507 and ∼946 nM, respectively. In contrast, glutamate‐enhanced [3H]MK‐801 binding was unaffected by conantokin‐G concentrations of <20 μM. At concentrations >5 μM, conantokin‐G effected a modest, noncompetitive inhibition of glycine‐stimulated [3H]MK‐801 binding and also produced a small enhancement of basal [3H]MK‐801 binding. Conan tokin‐G reduced (IC50∼1.08 μM) the NMDA‐stimulated accumulation of cyclic GMP in cerebellar granule cell cultures to basal values, but did not affect kainate‐mediated increases in cyclic GMP. These findings indicate that conantokin‐G acts as a noncompetitive NMDA antagonist through an allosteric inhibition of polyamine responses. The neurochemical profile of this polypeptide is distinct from previously described noncompetitive NMDA antagonists.

Original languageEnglish
Pages (from-to)1516-1521
Number of pages6
JournalJournal of Neurochemistry
Volume59
Issue number4
DOIs
StatePublished - Oct 1992
Externally publishedYes

Keywords

  • Conantokin‐G
  • Glycine
  • MK‐801
  • N‐Methyl‐D‐aspartate
  • Polyamines
  • Spermidine
  • Spermine

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