Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors

Fazio, F., Lionetto, L., Molinaro, G. , Bertrand, H.O., Acher, F., Ngomba, R.T., Notartomaso, S., Curini, M., Rosati, O., Scarselli, P., Di Marco, R.a, Battaglia, G., Bruno, V., Simmaco, M., Pin, J.P., Nicoletti, F. and Goudet, C. (2012) Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors. Molecular Pharmacology, 81 (5). pp. 643-656. ISSN 0026-895X

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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)cyclopropab-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.

Keywords:1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine, cinnabarinic acid, drug metabolite, kynurenine, lipopolysaccharide, metabotropic receptor 4, unclassified drug, animal cell, article, gene deletion, high performance liquid chromatography, human, human cell, metabolite, molecular model, mouse, mutagenesis, nerve cell, nonhuman, priority journal, tandem mass spectrometry, Animals, Cells, Cultured, Cyclic AMP, Glutamic Acid, Humans, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Oxazines, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate
Subjects:B Subjects allied to Medicine > B210 Pharmacology
B Subjects allied to Medicine > B140 Neuroscience
Divisions:College of Science > School of Pharmacy
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ID Code:22149
Deposited On:04 Feb 2016 19:30

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