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.
Highlights
G protein-coupled receptors (GPCRs) are an important target of innovative drug development for type 2 diabetes[1]
We examined whether the TRP channel blockers 2-aminoethyl diphenylborinate (2-APB), a nonselective TRP channel blocker and 3,5-bis(trifluoromethyl)pyrazole derivative 2 (BTP2), a selective TRP canonical (TRPC) channel blocker, inhibit the nonselective cation channels (NSCCs)-current increase induced by fasiglifam (Fig. 3a,b)
We found that G protein-coupled receptor 40 (GPR40) stimulation increases the NSCC current because of openings of TRPC3 channels and depolarizes the membrane followed by action potential firings in cooperation with KATP channel closure over sub-threshold concentrations of glucose
Summary
G protein-coupled receptors (GPCRs) are an important target of innovative drug development for type 2 diabetes[1]. G protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic beta-cell[2,3], and its agonistic stimulation enhances glucose-stimulated insulin secretion (GSIS), thereby being a promising therapeutic target in type 2 diabetes[4,5,6]. Incretin hormone glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP), a ligand of the Gs-coupled protein receptor of pancreatic beta-cell, stimulates adenylate cyclase and increases cytosolic cyclic adenosine 3′,5′-monophosphate (cAMP). We have reported that glucose and GLP-1 increase NSCC currents and cooperatively facilitate the depolarization of beta-cell membranes with the glucose-induced closure of ATP-sensitive potassium (KATP) channels[14]. (c) Fasiglifam-induced increase in NSCC current was observed in the absence of tolbutamide at a holding potential of −80 mV.
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