NONCOMPETITIVE INHIBITION OF N-METHYL-D-ASPARTATE BY CONANTOXIN-G - EVIDENCE FOR AN ALLOSTERIC INTERACTION AT POLYAMINE SITES

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 [H-3]MK-801 binding to extensively washed rat forebrain membranes in a noncompetitive manner with IC50 values of approximately 507 and approximately 946 nM, respectively. In contrast, glutamate-enhanced [H-3]MK-801 binding was unaffected by conantokin-G concentrations of less-than-or-equal-to 20-mu-M. At concentrations greater-than-or-equal-to 5-mu-M, conantokin-G effected a modest, noncompetitive inhibition of glycine-stimulated [H-3]MK-801 binding and also produced a small enhancement of basal [H-3]MK-801 binding. Conantokin-G reduced (IC50 approximately 1.08-mu-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.