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

ABSTRACT: FFAR1/GPR40 is a seven-transmembrane domain receptor (7TMR) expressed in pancreatic ? 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 ?-arrestins. Further, G protein- and ?-arrestin-based signaling can be differentially modulated by different ligands, thus eliciting ligand-specific responses ("biased agonism"). Whether GPR40 engages ?-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-?-arrestin interaction, with the synthetic GPR40 agonist TAK-875 being more effective than palmitate or oleate in recruiting ?-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 ?-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 ?-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.

SUBMITTER: Mancini AD

PROVIDER: S-EPMC4543669 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Mancini Arturo D AD Bertrand Gyslaine G Vivot Kevin K Carpentier Éric É Tremblay Caroline C Ghislain Julien J Bouvier Michel M Poitout Vincent V

The Journal of biological chemistry 20150708 34

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 modulate ...[more]

PMID: 26157145

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Project description:RATIONALE:MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize ?-adrenergic receptor (?AR) signaling, ?-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the ?-arrestin-biased ?AR ligand carvedilol, we previously showed that ?-arrestin1 (not ?-arrestin2)-biased ?1AR (not ?2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes ?-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. OBJECTIVE:Here, we investigate whether ?-arrestin-mediated ?AR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling. METHODS AND RESULTS:In mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a ?-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on ?2ARs and ?1ARs, respectively. Mechanistically, ?-arrestin 1 or 2 regulates maturation of three newly identified ?AR/?-arrestin-responsive miRs (?-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of ?-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, ?-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. CONCLUSIONS:Our findings indicate a novel role for ?AR-mediated ?-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.

Dataset Information

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

Publications

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

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