Novel selective ligands for free fatty acid receptors GPR120 and GPR40
Novel selective ligands for free fatty acid receptors GPR120 and GPR40
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DOI：
10.1007/s00210-009-0425-9
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发表时间：
2009-09-01
影响因子：
3.6
通讯作者：
Tsujimoto, Gozoh
中科院分区：
文献类型：
--
作者：
Hara, Takafumi;Hirasawa, Akira;Tsujimoto, Gozoh
GPR 120和GPR 40是G蛋白偶联受体，其内源性配体是中链和长链游离脂肪酸，并且它们被认为在胰岛素释放中起重要的生理作用。尽管最近在了解它们的作用方面取得了进展，但它们的药理学仍不清楚，迄今为止，除了中长链脂肪酸外，很少有GPR 120和GPR 40的特异性配体被报道。为了鉴定这些受体的新的选择性配体，通过分别监测诱导型和稳定表达细胞系中GPR 40和GPR 120的细胞外调节激酶（ERK）和[Ca 2 +]（i）应答，筛选了80多种天然化合物以及已知激活GPR 40的参比化合物MEDICA 16。MEDICA 16选择性地激活表达GPR 40的细胞中的[Ca 2 +]（i）应答，但不激活表达GPR 120的细胞中的[Ca 2 +]（i）应答。在测试的天然化合物中，grifolin衍生物，grifolic acid和grifolic acid methyl ether，促进GPR 120表达细胞中的ERK和[Ca 2 +]（i）反应，但不促进GPR 40表达细胞中的ERK和[Ca 2 +]（i）反应，并抑制GPR 120表达细胞中的α-亚麻酸（LA）诱导的ERK和[Ca 2 +]（i）反应。有趣的是，根据这些化合物的药理学特征，在内源性表达GPR 120的小鼠肠内分泌细胞系STC-1细胞中观察到胰高血糖素样肽-1分泌的相似特征。总之，这些研究鉴定了选择性GPR 40激动剂和几种GPR 120部分激动剂。这些化合物将为进一步研究GPR 40和GPR 120的生理和药理功能提供有用的探针。
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.