Discovery of Novel FFA4 (GPR120) Receptor Agonists with β-Arrestin2-Biased Characteristics

Li, Ang; Du, Yang; Zhu, Mengyuan; Tsai, Keng‐Chang; Xiao, Kunhong; Yu, Xiao; Sun, Junying; Du, Lüpei

doi:10.4155/fmc.15.160

Cited by 21 publications

(16 citation statements)

References 31 publications

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“…Different signaling pathways in different cell types were demonstrated with GW9508 and TUG-891 that recruited β-arrestin-2 in Caco-2 cells but not in STC-1 cells [ 43 ]. However, to fully elucidate the biological function of GPR120, the generation of selective biased agonists and assessment of signaling in different cell types are critical [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

et al. 2017

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The mechanism behind the glucose lowering effect occurring after specific activation of GPR120 is not completely understood. In this study, a potent and selective GPR120 agonist was developed and its pharmacological properties were compared with the previously described GPR120 agonist Metabolex-36. Effects of both compounds on signaling pathways and GLP-1 secretion were investigated in vitro. The acute glucose lowering effect was studied in lean wild-type and GPR120 null mice following oral or intravenous glucose tolerance tests. In vitro, in GPR120 overexpressing cells, both agonists signaled through Gαq, Gαs and the β-arrestin pathway. However, in mouse islets the signaling pathway was different since the agonists reduced cAMP production. The GPR120 agonists stimulated GLP-1 secretion both in vitro in STC-1 cells and in vivo following oral administration. In vivo GPR120 activation induced significant glucose lowering and increased insulin secretion after intravenous glucose administration in lean mice, while the agonists had no effect in GPR120 null mice. Exendin 9–39, a GLP-1 receptor antagonist, abolished the GPR120 induced effects on glucose and insulin following an intravenous glucose challenge. In conclusion, GLP-1 secretion is an important mechanism behind the acute glucose lowering effect following specific GPR120 activation.

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Section: Discussionmentioning

confidence: 99%

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

et al. 2017

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“…Therefore, GPR120 likely has a typical mechanism of activation observed in many GPCRs of the rhodopsin family. The validated GPR120 binding site, together with the improved homology model, could be further used for establishing the binding properties of a recently identified antagonist (Sparks et al 2014) and biased agonist (Li et al 2015). For instance, by introducing modifications in the cholecystokinin 2 (CCK2) receptor as well as in its biased antagonist suggested by modelling, Magnan and colleagues (Magnan et al 2013) were able to identify the key moiety in the ligand responsible for biased signalling and a microswitch of activation, involving M3.32 and Y7.43 that stabilizes the β-arrestin active state of the CCK2 receptor.…”

Section: ____________________________________________________________mentioning

confidence: 99%

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Tikhonova

2016

Free Fatty Acid Receptors

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Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.

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“…A recent study has demonstrated that eicosapentaenoic acid can prevent arterial calcification via GPR120 in klotho mutant mice (13). In addition, some small molecules have been found to activate the GPR120 receptor with an excellent activity (14).…”

mentioning

confidence: 99%

Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice

Ren

Chen

Wang

et al. 2019

The Journal of Immunology

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G protein–coupled receptor 120 (GPR120) has been shown to negatively regulate inflammation and apoptosis, but its role in cerebral ischemic injury remains unclear. Using an in vivo model of middle cerebral artery occlusion (MCAO) and an in vitro model of oxygen-glucose deprivation (OGD), we investigated the potential role and molecular mechanisms of GPR120 in focal cerebral ischemic injury. Increased GPR120 expression was observed in microglia and neurons following MCAO-induced ischemia in wild type C57BL/6 mice. Treatment with docosahexaenoic acid (DHA) inhibited OGD-induced inflammatory response in primary microglia and murine microglial BV2 cells, whereas silencing of GPR120 strongly exacerbated the inflammation induced by OGD and abolished the anti-inflammatory effects of DHA. Mechanistically, DHA inhibited OGD-induced inflammation through GPR120 interacting with β-arrestin2. In addition to its anti-inflammatory function, GPR120 also played a role in apoptosis as its knockdown impaired the antiapoptotic effect of DHA in OGD-induced rat pheochromocytoma (PC12) cells. Finally, using MCAO mouse model, we demonstrated that GPR120 activation protected against focal cerebral ischemic injury by preventing inflammation and apoptosis. Our study indicated that pharmacological targeting of GPR120 may provide a novel approach for the treatment of patients with ischemic stroke.

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Discovery of Novel FFA4 (GPR120) Receptor Agonists with β-Arrestin2-Biased Characteristics

Abstract: These compounds may serve as the useful toolkits for detecting differential biased mechanism and developing new candidate therapeutic agents of the FFA4 receptor.

Cited by 21 publications

References 31 publications

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

The acute glucose lowering effect of specific GPR120 activation in mice is mainly driven by glucagon-like peptide 1

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Activation of the Omega-3 Fatty Acid Receptor GPR120 Protects against Focal Cerebral Ischemic Injury by Preventing Inflammation and Apoptosis in Mice

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