| First Author | Usui R | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 15562 |
| PubMed ID | 31664108 | Mgi Jnum | J:284285 |
| Mgi Id | MGI:6389409 | Doi | 10.1038/s41598-019-52048-1 |
| Citation | Usui R, et al. (2019) GPR40 activation initiates store-operated Ca(2+) entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic beta-cells. Sci Rep 9(1):15562 |
| abstractText | The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic beta-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, beta-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 beta-cells. |
