Kynurenic Acid as a Ligand for Orphan G Protein-coupled Receptor GPR35*

By Jinghong Wang, Nicole Simonavicius, Xiaosu Wu, G. Swaminath, J. Reagan, H. Tian, L. Ling. Journal of Biological Chemistry, 2006

655 citations recorded by the source corpus.

Local catabolism of the essential amino acid tryptophan is considered an important mechanism in regulating immunological and neurological responses. The kynurenine pathway is the main route for the non-protein metabolism of tryptophan. The intermediates of the kynurenine pathway are present at micromolar concentrations in blood and are regulated by inflammatory stimuli. Here we show that GPR35, a previously orphan G protein-coupled receptor, functions as a receptor for the kynurenine pathway intermediate kynurenic acid. Kynurenic acid elicits calcium mobilization and inositol phosphate production in a GPR35-dependent manner in the presence of Gqi/o chimeric G proteins. Kynurenic acid stimulates [35S]guanosine 5′-O-(3-thiotriphosphate) binding in GPR35-expressing cells, an effect abolished by pertussis toxin treatment. Kynurenic acid also induces the internalization of GPR35. Expression analysis indicates that GPR35 is predominantly detected in immune cells and the gastrointestinal tract. Furthermore, we show that kynurenic acid inhibits lipopolysaccharide-induced tumor necrosis factor-α secretion in peripheral blood mononuclear cells. Our results suggest unexpected signaling functions for kynurenic acid through GPR35 activation.

Subfields: Biological Psychiatry, Physiology, Social Psychology

View Paper: https://www.semanticscholar.org/paper/3bed27df28a99cb2a3e23e07bd651b63f829ce26

How researchers see this paper

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In Biological Psychiatry

1. D. Munn
2. A. Mellor
3. W. Zou

In Physiology

1. A. Mellor
2. R. Ross
3. D. Munn

In Social Psychology

1. K. Mackie

Citations in the corpus

• International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2 (2010, background): “S binding to membranes from CHO cells stably expressing GPR84 (Wang et al., 2006a).”
• Impact of the Gut Microbiota on Intestinal Immunity Mediated by Tryptophan Metabolism (2018, background): “Based on elevated KA levels, anti-inflammatory effects of KA during inflammation, and increased expression of GPR35 in immune cells, several studies have suggested that KA may have important functions in immunological regulation via GPR35 activation and subsequent signaling (Wang et al., 2006).”
• The G protein-coupled receptor subset of the rat genome (2007, methodology): “These were systematically searched using keyword look-ups in Pubmed and BLAST in the NCBI's non-redundant (nr) database to find receptor deorphanization reports [26,76-85].”
• Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health (2017, background): “This receptor is expressed in human CD14monocytes, T cells, neutrophils, DCs, eosinophils, basophils and invariant NKT (iNKT) cells (13, 74).”
• Indoleamine 2,3-dioxygenase and tumor-induced tolerance. (2007, background): “The molecular mechanism by which these compounds exert their immunologic effects is not known, but at least one recent report has described a receptor able to bind a specific metabolite of tryptophan (kynurenic acid) (46).”