title: Guanine nucleotide modulation of [3H]TCP binding to the NMDA receptor complex.
abstract: Guanine nucleotides have been examined for their effect on [3H]1-[1-(2-thienyl)-cyclohexyl]-piperidine ([3H]TCP) binding to rat forebrain synaptic plasma membranes (SPM). We report that of the series of guanine nucleotides tested, GTP, GDP, 5'-guanylylimidodiphosphate (Gpp(NH)p) and 5'-guanylylmethylenediphosphate (Gpp(CH2)p) are significantly more potent at decreasing [3H]TCP binding than GMP, cyclic GMP, and guanosine. GTP, the most potent compound tested, inhibited basal [3H]TCP binding with an IC50 of 38.7 microM. Stimulation of [3H]TCP binding with either the N-methyl-D-aspartate (NMDA) agonist, L-glutamate, or Mg2+ was also inhibited by GTP. Addition of GTP resulted in a rightward shift in the glutamate dose-response curve and a decrease in the maximum level of stimulation. The Mg2+ stimulation of [3H]TCP binding was completely blocked by the addition of GTP. These results, coupled with the previous findings that guanine nucleotides inhibit the binding of L-[3H]glutamate to the NMDA recognition site (Monahan et al., 1988), indicate that guanine nucleotides antagonize NMDA receptor-mediated neurotransmission, at least in part, through their action (direct or indirect) on the NMDA recognition site and thus may be endogenous negative modulators of the NMDA receptor.
authors.affiliation: CNS Diseases Research, Division of G.D. Searle and Co., St. Louis, MO 63198.
authors.forename: W F
authors.initials: WF
authors.lastname: Hood
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
authors.forename: R P
authors.initials: RP
authors.lastname: Compton
authors.forename: J B
authors.initials: JB
authors.lastname: Monahan
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004492:Edetic Acid / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
chemical_list: D006150:Guanine Nucleotides; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D006160:Guanosine Triphosphate; C012058:tenocyclidine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D004492:Edetic Acid; D008274:Magnesium; D010622:Phencyclidine