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Molecular Pharmacology

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Research ArticleArticle

Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors

F. Fazio, L. Lionetto, G. Molinaro, H. O. Bertrand, F. Acher, R. T. Ngomba, S. Notartomaso, M. Curini, O. Rosati, P. Scarselli, R. Di Marco, G. Battaglia, V. Bruno, M. Simmaco, J. P. Pin, F. Nicoletti and C. Goudet
Molecular Pharmacology May 2012, 81 (5) 643-656; DOI: https://doi.org/10.1124/mol.111.074765
F. Fazio
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L. Lionetto
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G. Molinaro
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H. O. Bertrand
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F. Acher
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R. T. Ngomba
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S. Notartomaso
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M. Curini
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O. Rosati
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P. Scarselli
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R. Di Marco
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G. Battaglia
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V. Bruno
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M. Simmaco
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J. P. Pin
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F. Nicoletti
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C. Goudet
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Abstract

Cinnabarinic acid is an endogenous metabolite of the kynurenine pathway that meets the structural requirements to interact with glutamate receptors. We found that cinnabarinic acid acts as a partial agonist of type 4 metabotropic glutamate (mGlu4) receptors, with no activity at other mGlu receptor subtypes. We also tested the activity of cinnabarinic acid on native mGlu4 receptors by examining 1) the inhibition of cAMP formation in cultured cerebellar granule cells; 2) protection against excitotoxic neuronal death in mixed cultures of cortical cells; and 3) protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice after local infusion into the external globus pallidus. In all these models, cinnabarinic acid behaved similarly to conventional mGlu4 receptor agonists, and, at least in cultured neurons, the action of low concentrations of cinnabarinic acid was largely attenuated by genetic deletion of mGlu4 receptors. However, high concentrations of cinnabarinic acid were still active in the absence of mGlu4 receptors, suggesting that the compound may have off-target effects. Mutagenesis and molecular modeling experiments showed that cinnabarinic acid acts as an orthosteric agonist interacting with residues of the glutamate binding pocket of mGlu4. Accordingly, cinnabarinic acid did not activate truncated mGlu4 receptors lacking the N-terminal Venus-flytrap domain, as opposed to the mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). Finally, we could detect endogenous cinnabarinic acid in brain tissue and peripheral organs by high-performance liquid chromatography-tandem mass spectrometry analysis. Levels increased substantially during inflammation induced by lipopolysaccharide. We conclude that cinnabarinic acid is a novel endogenous orthosteric agonist of mGlu4 receptors endowed with neuroprotective activity.

Footnotes

  • This work was supported by a grant from the Era-net NEURON program (Neurodegeneration 2008: mGluRpatho).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.074765.

  • ABBREVIATIONS:

    CNS
    central nervous system
    NMDA
    N-methyl-d-aspartate
    mGlu
    metabotropic glutamate
    l-AP4
    l-(+)-2-amino-4-phosphonobutyric acid
    PHCCC
    N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide
    PPG
    (R,S)-4-phosphonophenylglycine
    DCG-IV
    (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine
    ACPT-I
    (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid
    IBMX
    3-isobutyl-1-methylxanthine
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    HEK
    human embryonic kidney
    InsP
    inositol phosphate
    DIV
    days in vitro
    TBS-T
    Tris-buffered saline/Tween 20
    LDH
    lactate dehydrogenase
    DA
    dopamine
    TH
    tyrosine hydroxylase
    EAE
    experimental autoimmune encephalomyelitis
    CSF
    cerebrospinal fluid
    HPLC
    high-performance liquid chromatography
    MS/MS
    tandem mass spectrometry
    LPS
    lipopolysaccharide
    LY379268
    (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid
    ANOVA
    analysis of variance
    PLSD
    protected least significant difference
    DMSO
    dimethyl sulfoxide.

  • Received July 13, 2011.
  • Accepted February 6, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (5)
Molecular Pharmacology
Vol. 81, Issue 5
1 May 2012
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Research ArticleArticle

Cinnabarinic Acid Activates mGlu4 Receptors

F. Fazio, L. Lionetto, G. Molinaro, H. O. Bertrand, F. Acher, R. T. Ngomba, S. Notartomaso, M. Curini, O. Rosati, P. Scarselli, R. Di Marco, G. Battaglia, V. Bruno, M. Simmaco, J. P. Pin, F. Nicoletti and C. Goudet
Molecular Pharmacology May 1, 2012, 81 (5) 643-656; DOI: https://doi.org/10.1124/mol.111.074765

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Research ArticleArticle

Cinnabarinic Acid Activates mGlu4 Receptors

F. Fazio, L. Lionetto, G. Molinaro, H. O. Bertrand, F. Acher, R. T. Ngomba, S. Notartomaso, M. Curini, O. Rosati, P. Scarselli, R. Di Marco, G. Battaglia, V. Bruno, M. Simmaco, J. P. Pin, F. Nicoletti and C. Goudet
Molecular Pharmacology May 1, 2012, 81 (5) 643-656; DOI: https://doi.org/10.1124/mol.111.074765
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