A G Protein-coupled Receptor Responsive to Bile Acids

• Published in: The Journal of biological chemistry Vol. 278; no. 11; pp. 9435 - 9440
• Main Authors: Kawamata, Yuji, Fujii, Ryo, Hosoya, Masaki, Harada, Masataka, Yoshida, Hiromi, Miwa, Masanori, Fukusumi, Shoji, Habata, Yugo, Itoh, Takashi, Shintani, Yasushi, Hinuma, Shuji, Fujisawa, Yukio, Fujino, Masahiko
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 14.03.2003
• Subjects: Amino Acid Sequence; Animals; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Cell Line; Cell Membrane - metabolism; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Cytokines - metabolism; Dose-Response Relationship, Drug; Genetic Vectors; Green Fluorescent Proteins; GTP-Binding Proteins - chemistry; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Luminescent Proteins - metabolism; Macrophages - metabolism; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases - metabolism; Molecular Sequence Data; Phagocytosis; Protein Binding; Rabbits; Rats; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Time Factors; Tissue Distribution; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M209706200

So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5′- O -3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.