title: Potentiation of Glucose-stimulated Insulin Secretion by the GPR40-PLC-TRPC Pathway in Pancreatic β-Cells.
abstract: G protein-coupled receptors (GPCRs) are expressed in pancreatic beta-cells. G protein-coupled receptor 40 (GPR40) contributes to medium- or long-chain fatty acid-induced amplification of glucose-stimulated insulin secretion (GSIS), and GPR40 agonists are promising therapeutic targets in type 2 diabetes. Recently, we demonstrated that glucagon-like peptide 1, a ligand of pancreatic GPCR, activates a class of nonselective cation channels (NSCCs) and enhances GSIS. The aim of the current study was to determine whether the GPR40 signal interacts with NSCCs. A GPR40 agonist (fasiglifam) potentiated GSIS at 8.3 and 16.7 mM glucose but not 2.8 mM glucose. The NSCC current was activated by fasiglifam at 5.6 mM glucose with 100 μM tolbutamide (-70 mV), and this activation was prevented by the presence of pyrazole-3 (transient receptor potential canonical; a TRPC3 channel blocker). Inhibitors of phospholipase C or protein kinase C (PKC) inhibited the increases in GSIS and the NSCC current induced by GPR40 stimulation. The present study demonstrates a novel mechanism for the regulation of insulin secretion by GPR40 agonist in pancreatic beta-cells. The stimulation of the GPR40-PLC/PKC-TRPC3 channel pathway potentiates GSIS by the depolarization of the plasma membrane in pancreatic beta-cell.
authors.affiliation: First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Amanuma, Omiya 1-847, Saitama 330-8503, Japan.
authors.forename: Hodaka
authors.initials: H
authors.lastname: Yamada
authors.affiliation: First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Amanuma, Omiya 1-847, Saitama 330-8503, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Amanuma, Omiya 1-847, Saitama 330-8503, Japan.
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Ito
authors.affiliation: Division of Integrative Physiology, Department of physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.affiliation: Division of Integrative Physiology, Department of physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
authors.affiliation: First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Amanuma, Omiya 1-847, Saitama 330-8503, Japan.
authors.forename: San-E
authors.initials: SE
authors.lastname: Ishikawa
authors.affiliation: First Department of Comprehensive Medicine, Jichi Medical University Saitama Medical Center, Amanuma, Omiya 1-847, Saitama 330-8503, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D004357:Drug Synergism; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000378:metabolism; D014044:Tolbutamide / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D001572:Benzofurans; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D050052:TRPC Cation Channels; D014044:Tolbutamide; D010738:Type C Phospholipases; D005947:Glucose