| CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. | |
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MedLine Citation:
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PMID: 10051528 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current study, we examined the pharmacological profile and site of action of the non-amino-acid antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in intracellular calcium at human mGluR1b (hmGluR1b) with an apparent IC50 of 6.5 microM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 microM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill coefficient of glutamate. Similarly, CPCCOEt did not displace [3H]glutamate binding to membranes prepared from mGluR1a-expressing cells. To elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and Ala818, located at the extracellular surface of transmembrane segment VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818 at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 microM), i.e., a gain of function. These data suggest that CPCCOEt represents a novel class of G protein-coupled receptor antagonists inhibiting receptor signaling without affecting ligand binding. We propose that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain. |
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Authors:
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S Litschig; F Gasparini; D Rueegg; N Stoehr; P J Flor; I Vranesic; L Prézeau; J P Pin; C Thomsen; R Kuhn |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Molecular pharmacology Volume: 55 ISSN: 0026-895X ISO Abbreviation: Mol. Pharmacol. Publication Date: 1999 Mar |
Date Detail:
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Created Date: 1999-03-25 Completed Date: 1999-03-25 Revised Date: 2005-11-17 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 453-61 Citation Subset: IM |
Affiliation:
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Novartis Pharma AG, Nervous System, Basel, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alanine
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metabolism Amino Acid Sequence Animals CHO Cells COS Cells Chromones / pharmacology* Cricetinae Excitatory Amino Acid Antagonists / pharmacology* Glutamic Acid / metabolism* Humans Molecular Sequence Data Mutagenesis, Site-Directed Rats Receptors, Metabotropic Glutamate / antagonists & inhibitors*, genetics, metabolism Recombinant Proteins / antagonists & inhibitors, genetics, metabolism Signal Transduction / drug effects* Threonine / metabolism |
| Chemical | |
Reg. No./Substance:
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0/7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; 0/Chromones; 0/Excitatory Amino Acid Antagonists; 0/Receptors, Metabotropic Glutamate; 0/Recombinant Proteins; 0/metabotropic glutamate receptor type 1; 56-41-7/Alanine; 56-86-0/Glutamic Acid; 72-19-5/Threonine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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