GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells
GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells
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DOI：
10.1038/s41598-019-52048-1
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发表时间：
2019-10
影响因子：
4.6
通讯作者：
Ryota Usui;D. Yabe;Muhammad Fauzi;Hisanori Goto;Ainur Botagarova;S. Tokumoto;H. Tatsuoka;Y. Tahara;Shizuka Kobayashi;T. Manabe;Y. Baba;T. Kurosaki;P. Herrera;M. Ogura;K. Nagashima;N. Inagaki
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作者：
Ryota Usui;D. Yabe;Muhammad Fauzi;Hisanori Goto;Ainur Botagarova;S. Tokumoto;H. Tatsuoka;Y. Tahara;Shizuka Kobayashi;T. Manabe;Y. Baba;T. Kurosaki;P. Herrera;M. Ogura;K. Nagashima;N. Inagaki
长链脂肪酸受体GPR 40在增强葡萄糖诱导的胰岛β细胞胰岛素分泌（GIIS）中起重要作用。先前的研究表明，GPR 40激活通过激活肌醇1，4，5-三磷酸（IP 3）受体增强内质网（ER）的Ca 2+释放。然而，它仍然是未知的ER Ca 2+释放通过IP 3受体与GIIS增强。近年来，基质相互作用分子（stromal interaction molecule，STIM）1被认为是钙库操纵的钙内流（store-operated Ca 2 +entry，SOCE）的关键调节因子，但其在GPR 40信号转导中的作用尚不清楚。我们表明，在分泌胰岛素的MIN 6细胞中，GPR 40介导的GIIS增强作用通过敲除IP 3受体1（IP 3 R1）、STIM 1或Ca 2+通道Orai 1而被消除。STIM 1和Orai 1敲低显著损害SOCE和GPR 40激动剂法昔利芬引起的细胞内Ca 2+增加。此外，β-细胞特异性STIM 1敲除小鼠不仅在分离的胰岛中而且在体内显示出受损的法格列芬介导的GIIS增强作用。这些结果表明，IP 3R 1/STIM 1/Orai 1通路在胰腺β细胞中GPR 40介导的SOCE起始和GIIS增强中起重要作用。
The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. Previous studies demonstrated that GPR40 activation enhances Ca2+release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca2+release via the IP3 receptor is linked to GIIS potentiation. Recently, stromal interaction molecule (STIM) 1 was identified as a key regulator of store-operated Ca2+entry (SOCE), but little is known about its contribution in GPR40 signaling. We show that GPR40-mediated potentiation of GIIS is abolished by knockdown of IP3 receptor 1 (IP3R1), STIM1 or Ca2+-channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca2+by the GPR40 agonist, fasiglifam. Furthermore, β-cell-specific STIM1 knockout mice showed impaired fasiglifam-mediated GIIS potentiation not only in isolated islets but alsoin vivo. These results indicate that the IP3R1/STIM1/Orai1 pathway plays an important role in GPR40-mediated SOCE initiation and GIIS potentiation in pancreatic β-cells.