Wang Jinghong, Simonavicius Nicole, Wu Xiaosu, Swaminath Gayathri, Reagan Jeff, Tian Hui, Ling Lei
Amgen Inc., South San Francisco, California 94080.
Amgen Inc., South San Francisco, California 94080.
J Biol Chem. 2006 Aug 4;281(31):22021-22028. doi: 10.1074/jbc.M603503200. Epub 2006 Jun 5.
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.
必需氨基酸色氨酸的局部分解代谢被认为是调节免疫和神经反应的重要机制。犬尿氨酸途径是色氨酸非蛋白质代谢的主要途径。犬尿氨酸途径的中间产物以微摩尔浓度存在于血液中，并受炎症刺激的调节。在此，我们表明GPR35（一种先前的孤儿G蛋白偶联受体）作为犬尿氨酸途径中间产物犬尿酸的受体发挥作用。在存在G(qi/o)嵌合G蛋白的情况下，犬尿酸以GPR35依赖的方式引发钙动员和肌醇磷酸生成。犬尿酸刺激表达GPR35的细胞中[35S]鸟苷5'-O-(3-硫代三磷酸)结合，百日咳毒素处理可消除该效应。犬尿酸还诱导GPR35的内化。表达分析表明，GPR35主要在免疫细胞和胃肠道中检测到。此外，我们表明犬尿酸抑制外周血单核细胞中脂多糖诱导的肿瘤坏死因子-α分泌。我们的结果表明犬尿酸通过GPR35激活具有意外的信号传导功能。
