GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic ß-cells.
Sci Rep
; 9(1): 15562, 2019 10 29.
Article
en En
| MEDLINE
| ID: mdl-31664108
ABSTRACT
The long-chain fatty acid receptor GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) from pancreatic ß-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, ß-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 ß-cells.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores Acoplados a Proteínas G
/
Receptores de Inositol 1,4,5-Trifosfato
/
Molécula de Interacción Estromal 1
/
Proteína ORAI1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Rep
Año:
2019
Tipo del documento:
Article
País de afiliación:
Japón