title: Xanthurenic acid binds to neuronal G-protein-coupled receptors that secondarily activate cationic channels in the cell line NCB-20.
abstract: Xanthurenic acid (XA) is a metabolite of the tryptophan oxidation pathway through kynurenine and 3-hydroxykynurenine. XA was until now considered as a detoxification compound and dead-end product reducing accumulation of reactive radical species. Apart from a specific role for XA in the signaling cascade resulting in gamete maturation in mosquitoes, nothing was known about its functions in other species including mammals. Based upon XA distribution, transport, accumulation and release in the rat brain, we have recently suggested that XA may potentially be involved in neurotransmission/neuromodulation, assuming that neurons presumably express specific XA receptors. Recently, it has been shown that XA could act as a positive allosteric ligand for class II metabotropic glutamate receptors. This finding reinforces the proposed signaling role of XA in brain. Our present results provide several lines of evidence in favor of the existence of specific receptors for XA in the brain. First, binding experiments combined with autoradiography and time-course analysis led to the characterization of XA binding sites in the rat brain. Second, specific kinetic and pharmacological properties exhibited by these binding sites are in favor of G-protein-coupled receptors (GPCR). Finally, in patch-clamp and calcium imaging experiments using NCB-20 cells that do not express glutamate-induced calcium signals, XA elicited specific responses involving activation of cationic channels and increases in intracellular Ca(2+) concentration. Altogether, these results suggest that XA, acting through a GPCR-induced cationic channel modulatory mechanism, may exert excitatory functions in various brain neuronal pathways.
authors.affiliation: Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, UMR_S INSERM U-1119, Université de Strasbourg, Faculté de Médecine, Strasbourg, France. omar@neuro-cnrs.unistra.fr
authors.forename: Omar
authors.initials: O
authors.lastname: Taleb
authors.forename: Mohammed
authors.initials: M
authors.lastname: Maammar
authors.forename: Daniel
authors.initials: D
authors.lastname: Brumaru
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.forename: Véronique
authors.initials: V
authors.lastname: Kemmel
authors.forename: Michel
authors.initials: M
authors.lastname: Maitre
authors.forename: Ayikoe Guy
authors.initials: AG
authors.lastname: Mensah-Nyagan
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002412:Cations; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D055724:Electrophysiological Phenomena / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014966:Xanthenes / Q000378:metabolism; D014977:Xanthurenates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D002412:Cations; C409648:Fluo 4; D007473:Ion Channels; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D014966:Xanthenes; D014977:Xanthurenates; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C028330:xanthurenic acid; D002118:Calcium