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

@article{Skolnick1992NoncompetitiveIO,
  title={Noncompetitive Inhibition of N‐Methyl‐D‐Aspartate by Conantokin‐G: Evidence for an Allosteric Interaction at Polyamine Sites},
  author={Phil Skolnick and Kathleen M. K. Boje and R Miller and Matthew W Pennington and Maria L. Maccecchini},
  journal={Journal of Neurochemistry},
  year={1992},
  volume={59}
}
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… 
Synthetic Analogues of Conantokin‐G: NMDA Antagonists Acting Through a Novel Polyamine‐Coupled Site
TLDR
Data are consistent with the hypothesis that this polypeptide acts at a unique, polyamine‐associated site on NMDA receptors, and the inability of con‐G to affect 5,7‐dichloro[3H]kynurenic acid, [3H],CGP‐39653, and [3h]ifenprodil binding.
NMDA receptor subunit‐dependent modulation by conantokin‐G and Ala(7)‐conantokin‐G
TLDR
It is concluded that the combinations of subunits that comprise the NMDA receptor complex influence conantokin and glutamate affinities and the nature of the responses to conantokins.
Amino acid determinants for NMDA receptor inhibition by conantokin‐T
Several derivatives of conantokin‐T (con‐T), a naturally occurring, γ‐carboxyglutamate (Gla)‐containing peptide with NMDA receptor (NMDAR) antagonist properties, were synthesized and evaluated for
Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.
TLDR
Results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors, and the unique subunit selectivity profile of Con G may explain its favorable in vivo profile compared with nonselective NMDA antagonists.
Conantokin G Is an NR 2 B-Selective Competitive Antagonist of N-Methyl-D-aspartate Receptors
TLDR
The results demonstrate that Con G is a subunit-specific competitive antagonist of NMDA receptors, and may explain its favorable in vivo profile compared with nonselective NMDA antagonists.
Spermine modulation of the glutamatenmda receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex
TLDR
The pharmacology of the N‐methyl‐d‐aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls, suggesting that the subunit composition of NMDA receptors may be locally variable.
Direct binding properties of conantokins to native N-methyl-d-aspartate receptors.
TLDR
The direct binding of [125I]Ala-con-G to adult rat brain sections revealed an anatomical distribution of binding sites in all regions known to contain the NR2B subunit of the NMDAR, and suggest that radiolabeled Ala- Con-G, and similar conantokin derivatives, may find utility as probes of NMD ARs in a variety of systems.
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References

SHOWING 1-10 OF 54 REFERENCES
Cooperative Modulation of [3H]MK‐801 Binding to the N‐Methyl‐d‐Aspartate Receptor‐Ion Channel Complex by l‐Glutamate, Glycine, and Polyamines
TLDR
High concentrations of l‐glutamate, glycine, or spermidine produced concentration‐dependent increases in specific [3H]MK‐801 binding due to a reduction in the Kd of the radioligand.
1‐Aminocyclopropane Carboxylic Acid: A Potent and Selective Ligand for the Glycine Modulatory Site of the N‐Methyl‐d‐Aspartate Receptor Complex
TLDR
Findings indicate that ACPC is a potent and selective ligand at the glycine modulatory site associated with the N‐methyl‐d‐aspartate receptor complex.
Polyamines regulate glycine interaction with the N‐methyl‐D‐aspartate receptor
TLDR
Kinetic studies showed that optimal concentrations of spermine and L‐glutamate reduced [3H]glycine association and dissociation rates by approximately fivefold and 30‐fold, respectively, and demonstrate that these compounds directly modulate glycine's interactions with the receptor complex.
N‐Methyl‐D‐Aspartate Receptors and Ethanol: Inhibition of Calcium Flux and Cyclic GMP Production
Abstract: Measurements of calcium uptake and cyclic GMP production by cerebellar granule cells grown in primary culture demonstrated that ethanol preferentially inhibited N‐methyl‐D‐aspartate (NMDA)
Effects of polyamines on the binding of [3H]MK-801 to the N-methyl-D-aspartate receptor: pharmacological evidence for the existence of a polyamine recognition site.
TLDR
It is concluded that these compounds are selective antagonists of the effects of spermine at the NMDA receptor and suggest that there may be a polyamine recognition site on theNMDA receptor complex.
Ifenprodil is a novel type of N-methyl-D-aspartate receptor antagonist: interaction with polyamines.
TLDR
Data indicate that ifenprodil may bind to the NMDA receptor in a state-dependent fashion and preferentially stabilize an inactivated form of the channel.
Ifenprodil and SL 82.0715 as cerebral antiischemic agents. III. Evidence for antagonistic effects at the polyamine modulatory site within the N-methyl-D-aspartate receptor complex.
TLDR
It is shown that ifenprodil and SL 82.0715 antagonize the effects of NMDA via a selective action at the recently described polyamine modulatory site.
The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.
TLDR
Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate, providing an explanation for the mechanism of action ofMK-801 as an anticonvulsant.
Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels.
  • J. E. Huettner, B. Bean
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
TLDR
MK-801 greatly reduced the channel activity elicited by application of N-Me-D-Asp but did not significantly alter the predominant unitary conductance, and the mean channel open time was reduced by MK-801 in a dose-dependent manner.
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