title: Characterization of [(3)H]Quisqualate binding to recombinant rat metabotropic glutamate 1a and 5a receptors and to rat and human brain sections.
abstract: We have investigated the binding properties of [(3)H]quisqualate to rat metabotropic glutamate (mGlu) 1a and 5a receptors and to rat and human brain sections. Saturation isotherms gave K:(D) values of 27 +/- 4 and 81 +/- 22 nM: for mGlu1a and mGlu5a receptors, respectively. Several compounds inhibited the binding to mGlu1a and mGlu5a receptors concentration-dependently. (S:)-4-Carboxyphenylglycine, (S:)-4-carboxy-3-hydroxyphenylglycine, and (R,S)-1-aminoindan-1,5-dicarboxylic acid, which completely inhibited [(3)H]quisqualate binding to the mGlu5a receptor, were inactive in a functional assay using this receptor. The distribution and abundance of binding sites in rat and human brain sections were studied by quantitative receptor radioautography and image analysis. Using 10 nM: [(3)H]quisqualate, a high density of binding was detected in various brain regions with the following rank order of increasing levels: medulla, thalamus, olfactory bulb, cerebral cortex, spinal cord dorsal horn, olfactory tubercle, dentate gyrus molecular layer, CA1-3 oriens layer of hippocampus, striatum, and cerebellar molecular layer. The ionotropic component of this binding could be inhibited by 30 microM: kainate, revealing the distribution of mGlu1+5 receptors. The latter were almost completely inhibited by the group I agonist (S:)-3,5-dihydroxyphenylglycine. The binding profile correlated well with the cellular sites of synthesis and regional expression of the respective group I receptor proteins revealed by in situ hybridization histochemistry and immunohistochemistry, respectively.
authors.affiliation: Pharma Division Preclinical CNS Research, F. Hoffmann-La Roche, Basel, Switzerland. vincent.mutel@roche.com
authors.forename: V
authors.initials: V
authors.lastname: Mutel
authors.forename: G J
authors.initials: GJ
authors.lastname: Ellis
authors.forename: G
authors.initials: G
authors.lastname: Adam
authors.forename: S
authors.initials: S
authors.lastname: Chaboz
authors.forename: A
authors.initials: A
authors.lastname: Nilly
authors.forename: J
authors.initials: J
authors.lastname: Messer
authors.forename: Z
authors.initials: Z
authors.lastname: Bleuel
authors.forename: V
authors.initials: V
authors.lastname: Metzler
authors.forename: P
authors.initials: P
authors.lastname: Malherbe
authors.forename: E J
authors.initials: EJ
authors.lastname: Schlaeger
authors.forename: B S
authors.initials: BS
authors.lastname: Roughley
authors.forename: R L
authors.initials: RL
authors.lastname: Faull
authors.forename: J G
authors.initials: JG
authors.lastname: Richards
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009928:Organ Specificity; D011799:Quinazolines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D014162:Transfection
chemical_list: C095756:1-aminoindan-1,5-dicarboxylic acid; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007189:Indans; D011799:Quinazolines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C112933:Ro 48-8587; C104077:metabotropic glutamate receptor type 1; C078245:4-carboxy-3-hydroxyphenylglycine; C023010:4-hydroxyphenylglycine; D016318:Quisqualic Acid; D007608:Kainic Acid; D002118:Calcium; D005998:Glycine