Noncompetitive inhibition of N-methyl-D-aspartate by conantokin-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 [3H]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 [3H]MK-801 binding was unaffected by conantokin-G concentrations of less than or equal to 20 microM. At concentrations greater than or equal to 5 microM, 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. Conantokin-G reduced (IC50 approximately 1.08 microM) 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.
Skolnick
P
P
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Boje
K
K
Miller
R
R
Pennington
M
M
Maccecchini
M L
ML
D000818:Animals; D001665:Binding Sites; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D020916:Conotoxins; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D020916:Conotoxins; D008978:Mollusk Venoms; D010456:Peptides, Cyclic; D011073:Polyamines; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C055407:conotoxin GV; D006152:Cyclic GMP