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Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules
Author(s) -
Briscoe Celia P,
Peat Andrew J,
McKeown Stephen C,
Corbett David F,
Goetz Aaron S,
Littleton Thomas R,
McCoy David C,
Kenakin Terry P,
Andrews John L,
Ammala Carina,
Fornwald James A,
Ignar Diane M,
Jenkinson Stephen
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706770
Subject(s) - free fatty acid receptor 1 , gpr120 , agonist , medicine , linoleic acid , fatty acid , endocrinology , receptor , free fatty acid receptor , hek 293 cells , secretion , insulin , intracellular , chemistry , biology , biochemistry , g protein coupled receptor , polyunsaturated fatty acid
1 Long chain fatty acids have recently been identified as agonists for the G protein‐coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small‐molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose‐stimulated insulin secretion in the MIN6 mouse pancreatic β ‐cell line. 2 GW9508 and linoleic acid both stimulated intracellular Ca 2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC 50 values of 7.32±0.03 and 5.65±0.06, respectively) or GPR120 (pEC 50 values of 5.46±0.09 and 5.89±0.04, respectively), but not in the parent HEK‐293 cell line. 3 GW1100 dose dependently inhibited GPR40‐mediated Ca 2+ elevations stimulated by GW9508 and linoleic acid (pIC 50 values of 5.99±0.03 and 5.99±0.06, respectively). GW1100 had no effect on the GPR120‐mediated stimulation of intracellular Ca 2+ release produced by either GW9508 or linoleic acid. 4 GW9508 dose dependently potentiated glucose‐stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl‐mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid‐stimulated insulin secretion was partially attenuated by GW1100. 5 These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small‐molecule GPR40 agonists are glucose‐sensitive insulin secretagogues.British Journal of Pharmacology (2006) 148 , 619–628. doi: 10.1038/sj.bjp.0706770