Effects of guanine nucleotides on N-methyl-D-aspartate receptor-ligand interactions.
Guanine nucleotides have been examined as to their effects on subclass-specific excitatory amino acid receptor-ligand interactions. Guanine nucleotides selectively inhibit L-[3H]glutamate binding to the N-methyl-D-aspartate (NMDA) recognition site while showing a lesser effect on [3H]kainate, [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and sodium-dependent L-[3H]glutamate binding. Of the series of guanine nucleotides tested in the inhibition of NMDA-specific L-[3H]glutamate binding, GTP, GDP, 5'-guanylylimidodiphosphate and 5'-guanylylmethylenediphosphate were significantly more potent than GMP, cyclic GMP and guanosine. Scatchard analysis indicates that the GTP inhibition (IC50 = 28 microM) of this NMDA-specific L-[3H]glutamate binding results from a decrease in the affinity of L-glutamate for the NMDA receptor whereas no alteration in the number of binding sites is observed. A kinetic analysis indicates that this decrease in affinity may be attributed to a decrease in association rate whereas no change in dissociation rate is observed. GTP (25 microM) lowers the affinities of both NMDA agonists (NMDA, L-glutamate, L-aspartate, and L-homocysteate) and antagonists (D-2-amino-5-phosphonovalerate, D-2-amino-7-phosphonoheptanoate, and D-2-aminoadipate). Pretreatment of the synaptic plasma membranes with either pertussis or cholera toxin had no significant effect on the GTP inhibition of NMDA-specific L-[3H] glutamate binding. The data suggest that guanine nucleotides can negatively modulate the NMDA receptor; however, the mechanism of this modulation is unclear.
Monahan
J B
JB
Searle Research and Development, Division of G.D. Searle & Co., St. Louis, Missouri 63198.
Hood
W F
WF
Michel
J
J
Compton
R P
RP
D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006150:Guanine Nucleotides / Q000494:pharmacology*; D066298:In Vitro Techniques; D018091:Receptors, AMPA; D011955:Receptors, Drug / Q000187:drug effects; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013570:Synaptic Membranes / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D006150:Guanine Nucleotides; D018091:Receptors, AMPA; D011955:Receptors, Drug; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D010566:Virulence Factors, Bordetella