β-Arrestin Recruitment and Biased Agonism at Free Fatty Acid Receptor 1.
J Biol Chem, 2015/8/21;290(34):21131-21140.
Mancini AD[1], Bertrand G[2], Vivot K[1], Carpentier É[3], Tremblay C[1], Ghislain J[1], Bouvier M[3], Poitout V[4]
Affiliations
PMID: 26157145DOI: 10.1074/jbc.M115.644450
Impact factor: 5.486
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
MeSH terms
Animals; Arrestins; Benzofurans; Biosensing Techniques; Cell Line, Tumor; Electron Spin Resonance Spectroscopy; GTP-Binding Protein alpha Subunits, Gq-G11; Gene Expression Regulation; HEK293 Cells; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Mice; Oleic Acid; Palmitic Acid; RNA, Small Interfering; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones; Tissue Culture Techniques; beta-Arrestin 2; beta-Arrestins
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