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Noncompetitive Inhibition of N ‐Methyl‐D‐Aspartate by Conantokin‐G: Evidence for an Allosteric Interaction at Polyamine Sites
Author(s) -
Skolnick Phil,
Boje Kathleen,
Miller Rachel,
Pennington Micheal,
Maccecchini MariaLuisa
Publication year - 1992
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1992.tb08468.x
Subject(s) - allosteric regulation , nmda receptor , spermine , non competitive inhibition , kainate receptor , spermidine , biology , biochemistry , polyamine , binding site , antagonism , dizocilpine , stereochemistry , chemistry , receptor , ampa receptor , enzyme
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 [ 3 H]MK‐801 binding to extensively washed rat forebrain membranes in a noncompetitive manner with IC 50 values of ∼507 and ∼946 n M , respectively. In contrast, glutamate‐enhanced [ 3 H]MK‐801 binding was unaffected by conantokin‐G concentrations of <20 μ M . At concentrations >5 μ M , conantokin‐G effected a modest, noncompetitive inhibition of glycine‐stimulated [ 3 H]MK‐801 binding and also produced a small enhancement of basal [ 3 H]MK‐801 binding. Conan tokin‐G reduced (IC 50 ∼1.08 μ M ) 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.