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dc.contributor.authorUsui, Ryota
dc.contributor.authorYabe, Daisuke
dc.contributor.authorFauzi, Muhammad
dc.contributor.authorGoto, Hisanori
dc.contributor.authorBotagarova, Ainur
dc.contributor.authorTokumoto, Shinsuke
dc.contributor.authorTatsuoka, Hisato
dc.contributor.authorTahara, Yumiko
dc.contributor.authorKobayashi, Shizuka
dc.contributor.authorManabe, Toshiya
dc.contributor.authorBaba, Yoshihiro
dc.contributor.authorKurosaki, Tomohiro
dc.contributor.authorHerrera, Pedro Luis
dc.contributor.authorOgura, Masahito
dc.contributor.authorNagashima, Kazuaki
dc.contributor.authorInagaki, Nobuya
dc.contributor.alternative臼井, 亮太
dc.contributor.alternative矢部, 大介
dc.contributor.alternative後藤, 久典
dc.contributor.alternative龍岡, 久登
dc.contributor.alternative小倉, 雅仁
dc.contributor.alternative長嶋, 一昭
dc.contributor.alternative稲垣, 暢也
dc.description.abstractThe 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 also in 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.
dc.publisherSpringer Science and Business Media LLC
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
dc.titleGPR40 activation initiates store-operated Ca²⁺ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells
dc.type.niitypeJournal Article
dc.identifier.jtitleScientific reports
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