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Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo.
J Pharmacol Exp Ther. 1989 Jul; 250(1):162-9.JP

Abstract

Guanine nucleotides were shown to alter N-methyl-d-aspartate (NMDA) receptor-effector coupling by competitive antagonism at the glutamate binding site, rather than via interaction with an intracellularly located GTP-binding protein. Thus, in contrast to known G-protein linked receptors, micromolar concentrations of guanine nucleotides and their analogs decreased both agonist [(3H]glutamate) and antagonist [(3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid binding to the NMDA receptor complex. The most potent compound, the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), was studied in detail. GDP beta S exhibited almost 200-fold selectivity for the glutamate recognition site vs. the strychnine-insensitive glycine binding site. IC50 values were 2.7 +/- 1.4 and 484 +/- 97 microM, respectively. GDP beta S also inhibited N-[1-(2-thienyl)cyclohexyl-3H]piperidine binding (IC50 was 28.0 +/- 3.7 microM) in an NMDA-reversible fashion. [3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid saturation binding studies revealed an increase in Kd from 263 +/- 49 (control) to 552 +/- 134 nM (8 microM GDP beta S) without any change in maximum binding (4.94 +/- 0.34 and 5.19 +/- 0.58 pmol/mg of protein, respectively). GDP beta S was also a competitive inhibitor of the following NMDA-stimulated responses: elevation of cyclic GMP in neonatal rat cerebellar slices, release of preloaded [3H]norepinephrine from superfused rat hippocampal slices and elevation of cytosolic calcium concentration in fura-2-loaded cultured rat forebrain neurons. IC50 values were 78.4, 53.4 and 1.6 microM, respectively. Finally, GDP beta S resembled known NMDA receptor antagonists in its ability to block NMDA receptor-induced seizures after i.c.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Baron BM
Merrell Dow Research Institute, Cincinnati, Ohio.
Dudley MW
No affiliation info available
McCarty DR
No affiliation info available
Miller FP
No affiliation info available
Reynolds IJ
No affiliation info available
Schmidt CJ
No affiliation info available

MeSH

AnimalsAspartic AcidBinding, CompetitiveBrainCalciumCerebellumCerebral CortexCyclic GMPCytosolGuanine NucleotidesHippocampusIntracellular MembranesKineticsMaleN-MethylaspartateNeuronsNorepinephrineRatsRats, Inbred StrainsReceptors, N-Methyl-D-AspartateReceptors, NeurotransmitterSynaptosomes

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2545857

Citation

Baron, B M., et al. "Guanine Nucleotides Are Competitive Inhibitors of N-methyl-D-aspartate at Its Receptor Site Both in Vitro and in Vivo." The Journal of Pharmacology and Experimental Therapeutics, vol. 250, no. 1, 1989, pp. 162-9.
Baron BM, Dudley MW, McCarty DR, et al. Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo. J Pharmacol Exp Ther. 1989;250(1):162-9.
Baron, B. M., Dudley, M. W., McCarty, D. R., Miller, F. P., Reynolds, I. J., & Schmidt, C. J. (1989). Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo. The Journal of Pharmacology and Experimental Therapeutics, 250(1), 162-9.
Baron BM, et al. Guanine Nucleotides Are Competitive Inhibitors of N-methyl-D-aspartate at Its Receptor Site Both in Vitro and in Vivo. J Pharmacol Exp Ther. 1989;250(1):162-9. PubMed PMID: 2545857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo. AU - Baron,B M, AU - Dudley,M W, AU - McCarty,D R, AU - Miller,F P, AU - Reynolds,I J, AU - Schmidt,C J, PY - 1989/7/1/pubmed PY - 1989/7/1/medline PY - 1989/7/1/entrez SP - 162 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 250 IS - 1 N2 - Guanine nucleotides were shown to alter N-methyl-d-aspartate (NMDA) receptor-effector coupling by competitive antagonism at the glutamate binding site, rather than via interaction with an intracellularly located GTP-binding protein. Thus, in contrast to known G-protein linked receptors, micromolar concentrations of guanine nucleotides and their analogs decreased both agonist [(3H]glutamate) and antagonist [(3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid binding to the NMDA receptor complex. The most potent compound, the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), was studied in detail. GDP beta S exhibited almost 200-fold selectivity for the glutamate recognition site vs. the strychnine-insensitive glycine binding site. IC50 values were 2.7 +/- 1.4 and 484 +/- 97 microM, respectively. GDP beta S also inhibited N-[1-(2-thienyl)cyclohexyl-3H]piperidine binding (IC50 was 28.0 +/- 3.7 microM) in an NMDA-reversible fashion. [3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid saturation binding studies revealed an increase in Kd from 263 +/- 49 (control) to 552 +/- 134 nM (8 microM GDP beta S) without any change in maximum binding (4.94 +/- 0.34 and 5.19 +/- 0.58 pmol/mg of protein, respectively). GDP beta S was also a competitive inhibitor of the following NMDA-stimulated responses: elevation of cyclic GMP in neonatal rat cerebellar slices, release of preloaded [3H]norepinephrine from superfused rat hippocampal slices and elevation of cytosolic calcium concentration in fura-2-loaded cultured rat forebrain neurons. IC50 values were 78.4, 53.4 and 1.6 microM, respectively. Finally, GDP beta S resembled known NMDA receptor antagonists in its ability to block NMDA receptor-induced seizures after i.c.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/2545857/Guanine_nucleotides_are_competitive_inhibitors_of_N_methyl_D_aspartate_at_its_receptor_site_both_in_vitro_and_in_vivo_ DB - PRIME DP - Unbound Medicine ER -