Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35.
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 G(qi/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-alpha secretion in peripheral blood mononuclear cells. Our results suggest unexpected signaling functions for kynurenic acid through GPR35 activation.
Wang
Jinghong
J
Amgen Inc., South San Francisco, California 94080.
Simonavicius
Nicole
N
Amgen Inc., South San Francisco, California 94080.
Wu
Xiaosu
X
Amgen Inc., South San Francisco, California 94080.
Swaminath
Gayathri
G
Amgen Inc., South San Francisco, California 94080.
Reagan
Jeff
J
Amgen Inc., South San Francisco, California 94080.
Tian
Hui
H
Amgen Inc., South San Francisco, California 94080.
Ling
Lei
L
Amgen Inc., South San Francisco, California 94080. Electronic address: lling@amgen.com.
D000818:Animals; D020013:Calcium Signaling; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000378:metabolism; D007295:Inositol Phosphates / Q000096:biosynthesis; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism*; D007963:Leukocytes, Mononuclear; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
C111379:GPR35 protein, human; C513986:GPR35 protein, mouse; C513985:GPR35 protein, rat; D007295:Inositol Phosphates; D008024:Ligands; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D014364:Tryptophan; D007736:Kynurenic Acid