4.5 Article

Novel selective ligands for free fatty acid receptors GPR120 and GPR40

期刊

出版社

SPRINGER
DOI: 10.1007/s00210-009-0425-9

关键词

GPCR; GPR120; GPR40; Free fatty acid receptor; Grifolin; GLP-1

资金

  1. Ministry of Education, Science, and Culture of Japan
  2. National Institute of Biomedical Innovation (NIBIO)
  3. Japan Health Science Foundation
  4. Ministry of Human Health and Welfare
  5. Mitsubishi Foundation
  6. Uehara Memorial Foundation
  7. Sankyo Foundation of Life Science
  8. Mochida Memorial Foundation
  9. Yakult Bio-Science Foundation
  10. Grants-in-Aid for Scientific Research [21390021] Funding Source: KAKEN

向作者/读者索取更多资源

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 alpha-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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