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J Biol Chem. 2015 Aug 21;290(34):21131-40. doi: 10.1074/jbc.M115.644450. Epub 2015 Jul 8.

β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1.

Author information

1
From the Montreal Diabetes Research Center, Research Center of the University of Montreal Hospital Center (CRCHUM), and Department of Medicine, University of Montreal, Quebec H2X 0A9, Canada.
2
the Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Universités de Montpellier 1 & 2, 34060 Montpellier, France, and.
3
the Department of Biochemistry and Molecular Medicine, University of Montreal, Quebec H3C 3J7, Canada.
4
From the Montreal Diabetes Research Center, Research Center of the University of Montreal Hospital Center (CRCHUM), and Department of Medicine, University of Montreal, Quebec H2X 0A9, Canada, the Department of Biochemistry and Molecular Medicine, University of Montreal, Quebec H3C 3J7, Canada vincent.poitout@umontreal.ca.

Abstract

FFAR1/GPR40 is a seven-transmembrane domain receptor (7TMR) expressed in pancreatic β cells and activated by FFAs. Pharmacological activation of GPR40 is a strategy under consideration to increase insulin secretion in type 2 diabetes. GPR40 is known to signal predominantly via the heterotrimeric G proteins Gq/11. However, 7TMRs can also activate functionally distinct G protein-independent signaling via β-arrestins. Further, G protein- and β-arrestin-based signaling can be differentially modulated by different ligands, thus eliciting ligand-specific responses ("biased agonism"). Whether GPR40 engages β-arrestin-dependent mechanisms and is subject to biased agonism is unknown. Using bioluminescence resonance energy transfer-based biosensors for real-time monitoring of cell signaling in living cells, we detected a ligand-induced GPR40-β-arrestin interaction, with the synthetic GPR40 agonist TAK-875 being more effective than palmitate or oleate in recruiting β-arrestins 1 and 2. Conversely, TAK-875 acted as a partial agonist of Gq/11-dependent GPR40 signaling relative to both FFAs. Pharmacological blockade of Gq activity decreased FFA-induced insulin secretion. In contrast, knockdown or genetic ablation of β-arrestin 2 in an insulin-secreting cell line and mouse pancreatic islets, respectively, uniquely attenuated the insulinotropic activity of TAK-875, thus providing functional validation of the biosensor data. Collectively, these data reveal that in addition to coupling to Gq/11, GPR40 is functionally linked to a β-arrestin 2-mediated insulinotropic signaling axis. These observations expose previously unrecognized complexity for GPR40 signal transduction and may guide the development of biased agonists showing improved clinical profile in type 2 diabetes.

KEYWORDS:

FFAR1/GPR40; G protein-coupled receptor (GPCR); Islet of Langerhans; Type 2 diabetes; arrestin; biased agonism; cell signaling; insulin secretion

PMID:
26157145
PMCID:
PMC4543669
DOI:
10.1074/jbc.M115.644450
[Indexed for MEDLINE]
Free PMC Article

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