Abstract
GPR120 and GPR40 are G-protein-coupled receptors whose endogenous ligands are medium- and long-chain free fatty acids, and they are thought to play an important physiological role in insulin release. Despite recent progress in understanding their roles, much still remains unclear about their pharmacology, and few specific ligands for GPR120 and GPR40 besides medium- to long-chain fatty acids have been reported so far. To identify new selective ligands for these receptors, more than 80 natural compounds were screened, together with a reference compound MEDICA16, which is known to activate GPR40, by monitoring the extracellular regulated kinase (ERK) and [Ca2+]i responses in inducible and stable expression cell lines for GPR40 and GPR120, respectively. MEDICA16 selectively activated [Ca2+]i response in GPR40-expressing cells but not in GPR120-expressing cells. Among the natural compounds tested, grifolin derivatives, grifolic acid and grifolic acid methyl ether, promoted ERK and [Ca2+]i responses in GPR120-expressing cells, but not in GPR40-expressing cells, and inhibited the α-linolenic acid (LA)-induced ERK and [Ca2+]i responses in GPR120-expressing cells. Interestingly, in accordance with the pharmacological profiles of these compounds, similar profiles of glucagon-like peptide-1 secretion were seen for mouse enteroendocrine cell line, STC-1 cells, which express GPR120 endogenously. Taken together, these studies identified a selective GPR40 agonist and several GPR120 partial agonists. These compounds would be useful probes to further investigate the physiological and pharmacological functions of GPR40 and GPR120.
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Acknowledgements
This work was supported in part by research grants from the Scientific Fund of the Ministry of Education, Science, and Culture of Japan (to G.T.), the Program for Promotion of Fundamental Studies in Health Sciences of National Institute of Biomedical Innovation (NIBIO) (to G.T.), the Japan Health Science Foundation and the Ministry of Human Health and Welfare (to G.T.), in part by the Mitsubishi Foundation, Uehara Memorial Foundation, the Sankyo Foundation of Life Science (to G.T.), and the Mochida Memorial Foundation for Medical and Pharmaceutical Research and the Yakult Bio-Science Foundation (to A.H.).
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Hara, T., Hirasawa, A., Sun, Q. et al. Novel selective ligands for free fatty acid receptors GPR120 and GPR40. Naunyn-Schmied Arch Pharmacol 380, 247–255 (2009). https://doi.org/10.1007/s00210-009-0425-9
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DOI: https://doi.org/10.1007/s00210-009-0425-9