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

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