Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells
Open Access
- 1 December 2008
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 155 (7), 1056-1065
- https://doi.org/10.1038/bjp.2008.337
Abstract
Background and purpose: GPR119 is a G protein‐coupled receptor that is preferentially expressed in islet cells and mediates insulin secretion. Oleoyl‐lysophosphatidylcholine and oleoylethanolamide (OEA) act as endogenous ligands for this receptor, whereas PSN375963 and PSN632408 are two recently reported synthetic agonists. In this study, we explored mechanisms underlying GPR119‐induced insulin secretion. In addition, we assessed the potential utility of the synthetic agonists as tools for exploring GPR119 biology. Experimental approach: We examined natural and synthetic GPR119 agonist activity at GPR119 in MIN6c4 and RINm5f insulinoma cells. We evaluated insulin secretion, intracellular calcium [Ca2+]i, ion channel involvement and levels of cAMP. Key results: We report that increases in insulin secretion induced by OEA were associated with increased cAMP and a potentiation of glucose‐stimulated increases in [Ca2+]i. We also demonstrate that ATP‐sensitive K+ and voltage‐dependent calcium channels were required for GPR119‐mediated increases in glucose‐stimulated insulin secretion. In contrast to OEA, the synthetic GPR119 agonist PSN375963 and PSN632408 have divergent effects on insulin secretion, cAMP and intracellular calcium in MIN6c4 cells. Conclusions and implications: The endogenous ligand OEA signals through GPR119 in a manner similar to glucagon‐like peptide‐1 (GLP‐1) and its receptor with respect to insulin secretion, [Ca2+]i and cAMP. In addition, PSN375963 and PSN632408 substantially differ from OEA and from one another. These studies suggest that the commercially available synthetic agonists, although they do activate GPR119, may also activate GPR119‐independent pathways and are thus unsuitable as GPR119‐specific pharmacological tools. British Journal of Pharmacology (2008) 155, 1056–1065; doi:10.1038/bjp.2008.337; published online 25 August 2008Keywords
This publication has 24 references indexed in Scilit:
- Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agentsCell Metabolism, 2006
- Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activityAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
- Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptorBiochemical and Biophysical Research Communications, 2004
- Oleoylethanolamide Stimulates Lipolysis by Activating the Nuclear Receptor Peroxisome Proliferator-activated Receptor α (PPAR-α)Journal of Biological Chemistry, 2004
- Food intake is inhibited by oral oleoylethanolamideJournal of Lipid Research, 2004
- Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell ApoptosisJournal of Biological Chemistry, 2003
- Peroxisome Proliferator-Activated Receptors: Nuclear Control of MetabolismEndocrine Reviews, 1999
- FLIPR: A New Instrument for Accurate, High Throughput Optical ScreeningSLAS Discovery, 1996
- Immunocytochemical localization of alpha-protein kinase C in rat pancreatic beta-cells during glucose-induced insulin secretion.The Journal of cell biology, 1992
- Biochemical mechanisms involved in monomethyl succinate-induced insulin secretionEndocrinology, 1992