Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules
Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules
复制标题
DOI：
10.1038/sj.bjp.0706770
复制
发表时间：
2006-07-01
影响因子：
7.3
通讯作者：
Jenkinson, Stephen
中科院分区：
文献类型：
--
作者：
Briscoe, Celia P.;Peat, Andrew J.;Jenkinson, Stephen
1长链脂肪酸最近被鉴定为G蛋白偶联受体GPR 40和GPR 120的激动剂。在这里，我们提出的第一个描述GW 9508，一个小分子激动剂的脂肪酸受体GPR 40和GPR 120。此外，我们还描述了选择性GPR 40拮抗剂GW 1100的药理学。这些分子用于进一步研究GPR 40在MIN 6小鼠胰腺β细胞系中葡萄糖刺激的胰岛素分泌中的作用。2 GW 9508和亚油酸均刺激表达GPR 40的人胚肾（HEK）293细胞中的细胞内Ca 2+动员（pEC（50）值为7.32 +/- 0.03和5.65 +/- 0.06，或GPR 120（pEC（50）值分别为5.46 +/-0.09和5.89 +/-0.04），但在亲本HEK-293细胞系中没有。3 GW 1100剂量依赖性地抑制由GW 9508和亚油酸刺激的GPR 40介导的Ca 2+升高（pIC（50）值为5.99 +/-03和5.99 +/-0.06）。GW 1100对GPR 120介导的GW 9508或亚油酸产生的细胞内Ca 2+释放刺激没有影响。4 GW 9508剂量依赖性地增强MIN 6细胞中葡萄糖刺激的胰岛素分泌，但在原代大鼠或小鼠胰岛中没有。此外，GW 9508能够增强KCl介导的MIN 6细胞中胰岛素分泌的增加。GW 9508对胰岛素分泌的影响被GW 1100逆转，而亚油酸刺激的胰岛素分泌被GW 1100部分减弱。5这些结果进一步证明了GPR 40与脂肪酸急性增强胰岛素分泌的能力之间的联系，并证明小分子GPR 40激动剂是葡萄糖敏感的胰岛素促分泌剂。
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 beta-cell line.2 GW9508 and linoleic acid both stimulated intracellular Ca2+ 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 Ca2+ 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 Ca2+ 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.