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Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism
Author(s) -
Li Yang,
Hu Nan,
Yang Dan,
Oxenkrug Gregory,
Yang Qing
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14026
Subject(s) - foxo1 , melatonin , kynurenine , kinase , phosphorylation , kynurenine pathway , signal transduction , indoleamine 2,3 dioxygenase , serotonin , tryptophan hydroxylase , biology , microbiology and biotechnology , protein kinase b , tryptophan , biochemistry , endocrinology , receptor , amino acid , serotonergic
Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC 12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other. Melatonin, the end product of the serotonin pathway, played an important role in tryptophan metabolism by affecting both key enzymes of the two pathways. Melatonin treatment induced the expression of indole‐2,3‐dioxygenase 1 ( IDO 1) and enhanced the activity of the IDO 1 promoter while decreasing the expression of arylalkylamine N ‐acetyl transferase. Melatonin treatment up‐regulated the expression of forkhead box protein O1 (FoxO1) and enhanced the binding of FoxO1 to the IDO 1 promoter. FoxO1 was shown to be a new regulator for IDO 1 expression. Melatonin treatment decreased the phosphorylation of FoxO1 by extracellular signal‐regulated kinases 1 and 2 and protein kinase B (Akt) and increased the phosphorylation of binding protein 14‐3‐3 by c‐Jun N‐terminal kinase ( JNK ), and thus the complex of FoxO1–14‐3‐3 in the cytoplasm was disassembled and FoxO1 was relocated to the nucleus to induce IDO 1 expression. The JNK signaling pathway played an important role in melatonin‐induced IDO 1 up‐regulation. In conclusion, this study suggests a link between melatonin, JNK , FoxO1 and IDO 1 that acts as a potential balance regulator of tryptophan metabolism, and offers a new approach to treat diseases related to dysregulation of tryptophan metabolism.