GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells

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 Ca 2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphospha...

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Published in:Scientific reports Vol. 9; no. 1; pp. 1 - 11
Main Authors: Usui, Ryota, Yabe, Daisuke, Fauzi, Muhammad, Goto, Hisanori, Botagarova, Ainur, Tokumoto, Shinsuke, Tatsuoka, Hisato, Tahara, Yumiko, Kobayashi, Shizuka, Manabe, Toshiya, Baba, Yoshihiro, Kurosaki, Tomohiro, Herrera, Pedro Luis, Ogura, Masahito, Nagashima, Kazuaki, Inagaki, Nobuya
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 29.10.2019
Nature Publishing Group
Subjects:
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14/28
631/443/319/1642
631/443/319/1642/137
64/60
Beta cells
Calcium (intracellular)
Calcium (reticular)
Calcium channels
Calcium influx
Endoplasmic reticulum
Humanities and Social Sciences
Inositol 1,4,5-trisphosphate receptors
Insulin
Insulin secretion
multidisciplinary
Orai1 protein
Pancreas
Science
Science (multidisciplinary)
Secretion
STIM1 protein
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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 Ca 2+ release from the endoplasmic reticulum (ER) by activating inositol 1,4,5-triphosphate (IP3) receptors. However, it remains unknown how ER Ca 2+ 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 Ca 2+ 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 Ca 2+ -channel Orai1 in insulin-secreting MIN6 cells. STIM1 and Orai1 knockdown significantly impaired SOCE and the increase of intracellular Ca 2+ 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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-52048-1