Dataset Information

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

ABSTRACT: The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic ?-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, ?-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 ?-cells.

SUBMITTER: Usui R

PROVIDER: S-EPMC6820554 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Usui Ryota R Yabe Daisuke D Fauzi Muhammad M Goto Hisanori H Botagarova Ainur A Tokumoto Shinsuke S Tokumoto Shinsuke S Tatsuoka Hisato H Tahara Yumiko Y Kobayashi Shizuka S Manabe Toshiya T Baba Yoshihiro Y Kurosaki Tomohiro T Herrera Pedro Luis PL Ogura Masahito M Nagashima Kazuaki K Inagaki Nobuya N

Scientific reports 20191029 1

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 identi ...[more]

PMID: 31664108

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Project description:Excessive cardiac fibrosis, characterized by increased collagen-rich extracellular matrix (ECM) deposition, is a major predisposing factor for mechanical and electrical dysfunction in heart failure (HF). The human ventricular fibroblast (hVF) remodeling mechanisms that cause excessive collagen deposition in HF are unclear, although reports suggest a role for intracellular free Ca2+ in fibrosis. Therefore, we determined the association of differences in cellular Ca2+ dynamics and collagen secretion/deposition between hVFs from failing and normal (control) hearts. Histology of left ventricle sections (Masson trichrome) confirmed excessive fibrosis in HF versus normal. In vitro, hVFs from HF showed increased secretion/deposition of soluble collagen in 48 h of culture compared with control [85.9±7.4 µg/106 cells vs 58.5±8.8 µg/106 cells, P<0.05; (Sircol™ assay)]. However, collagen gene expressions (COL1A1 and COL1A2; RT-PCR) were not different. Ca2+ imaging (fluo-3) of isolated hVFs showed no difference in the thapsigargin-induced intracellular Ca2+ release capacity (control 16±1.4% vs HF 17±1.1%); however, Ca2+ influx via store-operated Ca2+ entry/Ca2+ release-activated channels (SOCE/CRAC) was significantly (P≤0.05) greater in HF-hVFs (47±3%) compared with non-failing (35±5%). Immunoblotting for ICRAC channel components showed increased ORAI1 expression in HF-hVFs compared with normal without any difference in STIM1 expression. The Pearson's correlation coefficient for co-localization of STIM1/ORAI1 was significantly (P<0.01) greater in HF (0.5±0.01) than control (0.4±0.01) hVFs. The increase in collagen secretion of HF versus control hVFs was eliminated by incubation of hVFs with YM58483 (10 µM), a selective ICRAC inhibitor, for 48 h (66.78±5.87 µg/106 cells vs 55.81±7.09 µg/106 cells, P=0.27). In conclusion, hVFs from HF have increased collagen secretion capacity versus non-failing hearts and this is related to increase in Ca2+ entry via SOCE and enhanced expression of ORAI, the pore-forming subunit. Therapeutic inhibition of SOCE may reduce the progression of cardiac fibrosis/HF.

Dataset Information

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

Publications

GPR40 activation initiates store-operated Ca<sup>2+</sup> entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells.

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Dataset Information

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

Publications

GPR40 activation initiates store-operated Ca<sup>2+</sup> entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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