Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors
Copyright policy )Cinnabarinic Acid, an Endogenous Metabolite of the Kynurenine Pathway, Activates Type 4 Metabotropic Glutamate Receptors
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.
- Inserm France
- Sapienza University of Rome Italy
- University of Montpellier France
- University of Perugia Italy
- University of Paris France
Male, Models, Molecular, 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,2R,3R)-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., MESH: Kynurenine, animal cell, Inbred C57BL, Receptors, Metabotropic Glutamate, Rats, Sprague-Dawley, Mice, Models, Receptors, MESH: Models, MESH: Receptors, Metabotropic Glutamate, Cyclic AMP, MESH: Animals, MESH: Cyclic AMP, Cells, Cultured, Kynurenine, MESH: Cells, Cultured, POSITIVE ALLOSTERIC MODULATOR, CEREBELLAR GRANULE CELLS, MOLECULAR DETERMINANTS, QUINOLINIC ACID, MGLUR4 SUBTYPE, RAT-BRAIN, IN-VIVO, MICE, TRYPTOPHAN, INDUCTION, lipopolysaccharide, article, MESH: Glutamic Acid, unclassified drug, priority journal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], nerve cell, mutagenesis, 570, high performance liquid chromatography, MESH: Rats, 3, Cells, 1, metabolite, 2, 610, Glutamic Acid, metabotropic receptor 4, tandem mass spectrometry, Oxazines, Animals, Humans, human, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, B210 - Pharmacology, mouse, nonhuman, MESH: Humans, gene deletion, human cell, 6 tetrahydro 1 methyl 4 phenylpyridine, Molecular, MESH: Male, kynurenine, Rats, Mice, Inbred C57BL, B140 - Neuroscience, cinnabarinic acid, drug metabolite, Sprague-Dawley, molecular model, MESH: Oxazines
Male, Models, Molecular, 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,2R,3R)-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., MESH: Kynurenine, animal cell, Inbred C57BL, Receptors, Metabotropic Glutamate, Rats, Sprague-Dawley, Mice, Models, Receptors, MESH: Models, MESH: Receptors, Metabotropic Glutamate, Cyclic AMP, MESH: Animals, MESH: Cyclic AMP, Cells, Cultured, Kynurenine, MESH: Cells, Cultured, POSITIVE ALLOSTERIC MODULATOR, CEREBELLAR GRANULE CELLS, MOLECULAR DETERMINANTS, QUINOLINIC ACID, MGLUR4 SUBTYPE, RAT-BRAIN, IN-VIVO, MICE, TRYPTOPHAN, INDUCTION, lipopolysaccharide, article, MESH: Glutamic Acid, unclassified drug, priority journal, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], nerve cell, mutagenesis, 570, high performance liquid chromatography, MESH: Rats, 3, Cells, 1, metabolite, 2, 610, Glutamic Acid, metabotropic receptor 4, tandem mass spectrometry, Oxazines, Animals, Humans, human, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, B210 - Pharmacology, mouse, nonhuman, MESH: Humans, gene deletion, human cell, 6 tetrahydro 1 methyl 4 phenylpyridine, Molecular, MESH: Male, kynurenine, Rats, Mice, Inbred C57BL, B140 - Neuroscience, cinnabarinic acid, drug metabolite, Sprague-Dawley, molecular model, MESH: Oxazines
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