title: Role of histidyl residues in the binding of ligands to the porcine N-methyl-D-aspartate receptor.
abstract: Possible involvement of histidyl residues in the binding of ligands to ionotropic glutamate receptors and to modulatory sites on the N-methyl-D-aspartate (NMDA) receptor was assessed in porcine cortical synaptic plasma membranes after covalent modification with diethyl pyrocarbonate (DEPC). Binding of [3H]glutamate to the NMDA sites was enhanced but to the 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate receptors unaffected by 1 and 5 mM DEPC. Binding of 3-[(R)-carboxypiperazin-4-yl]-[1,2-(3)H]propyl-1-phosphonate ([3H]CPP) was reduced in a dose-dependent manner by DEPC and the activation of binding by 1-hydroxy-3-amino-2-pyrrolidone (HA-966) blocked by 10 mM DEPC. DEPC reduced the strychnine-insensitive binding of [3H]glycine and the glycine- and glutamate-activated binding of [3H]dizocilpine. Protection experiments indicated that histidyl residues are directly involved in the binding of glycine (but not HA-966) and allosterically modulate the binding of glutamate, CPP and dizocilpine. The results corroborate the existence of agonist- and antagonist-preferring sites or conformational states of the NMDA receptors.
authors.affiliation: Tampere Brain Research Center, University of Tampere, Medical School, Finland.
authors.forename: Z
authors.initials: Z
authors.lastname: Jenei
authors.forename: V
authors.initials: V
authors.lastname: Varga
authors.forename: R
authors.initials: R
authors.lastname: Janáky
authors.forename: P
authors.initials: P
authors.lastname: Saransaari
authors.forename: S S
authors.initials: SS
authors.lastname: Oja
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006639:Histidine / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008024:Ligands; D016202:N-Methylaspartate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013552:Swine; D013570:Synaptic Membranes / Q000737:chemistry / Q000378:metabolism; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007476:Ionophores; D008024:Ligands; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D018698:Glutamic Acid; D006639:Histidine; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D004047:Diethyl Pyrocarbonate; D007608:Kainic Acid