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Abstract
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 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.
Highlights
The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells
Since GPR40 signaling is known to activate phospholipase C (PLC) and to produce IP35, IP3 receptor (IP3R) involvement in fas-mediated GIIS potentiation was investigated. It was previously demonstrated in various cell types that IP3Rs activation facilitated Ca2+ release from the ER27,28, and that IP3-induced endoplasmic reticulum (ER) Ca2+ release is augmented when the glucose level is elevated in β-cells[29], suggesting that they may be attractive targets to clarify the requirement of glucose in fas-mediated GIIS potentiation
Because IP3 receptor (IP3R) 1 and IP3R3 are expressed in mouse islets and MIN6 cells (Figs 1B and S1A) and IP3 receptor 1 (IP3R1) is known to be activated by IP3 and ATP27,30, involvement of IP3Rs in fas-mediated GIIS potentiation was tested using the IP3R inhibitor xestospongin C
Summary
The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic β-cells. The current study aims to establish the mechanism by which the GPR40 signal potentiates GIIS and to clarify the role of SOCE in GPR40 signaling using siRNA transfected MIN6 cells and β-cell-specific STIM1 knockout mice. Because IP3 receptor (IP3R) 1 and IP3R3 are expressed in mouse islets and MIN6 cells (Figs 1B and S1A) and IP3R1 is known to be activated by IP3 and ATP27,30, involvement of IP3Rs in fas-mediated GIIS potentiation was tested using the IP3R inhibitor xestospongin C.
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