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Results indicate that FFAR4 plays a more critical role than FFAR1 in mediation of fat-regulated neurotensin release from neuroendocrine cells and in inhibitory crosstalk between MEK/ERK1/2 and AMPK in the control of NT release downstream of FFAR1 and FFAR4.
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These results suggest that the cell motile and growth activities may be positively regulated through the induction of GPR40 by the long-term TAM treatment in MCF-7 cells.
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Study conclude that free fatty acids are regulators of not only insulin but also glucagon and somatostatin secretion at fasting glucose concentrations from human islets and that FFAR1 is crucial in this effect. This implies that the effect of FFAR1 on hormone secretion is not restricted to amplification at elevated glucose concentrations, as previously reported, but rather fuel substrate dependent.
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Study reports the 2.76-A crystal structure of human GPR40 complexed with compound 1 bound in a second structurally distinct allosteric site, located at the receptor side facing the membrane lipophilic environment. Binding of compound 1 stabilizes the intracellular loop 2 (ICL2) of GPR40 in a helical conformation. Mutagenesis studies in ICL2 shows that this loop is important for Gs alpha subunit coupling.
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Data indicate that 20-HETE and FFAR1 function together in a positive feedback loop to enhance glucose-stimulated insulin secretion (GSIS).
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Comparison with an additional 2.2-A structure of the human GPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix.
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Results show that GPR40 negatively regulated the cell motile and invasive activities of HT1080 cells suggesting that GPR40 negatively regulates the tumor progression of fibrosarcoma cells.
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Brain free long-chain fatty acids-GPR40/FFA1 signaling might have an important role in the modulation of endogenous pain control systems. (review)
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It regulates insulin secretion in pancreatic beta-cells. (review)
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Data from molecular docking simulations suggest that the binding pocket of GPR40 exhibits binding of free fatty acids (FFA) with chain lengths of C15 or fewer; for FFA with lengths longer than C15, part of alkyl chain extends out of binding pocket.
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GPR120 negatively and GPR40 positively regulate cellular functions during tumor progression in lung cancer cells.
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Increased membrane permeability induced by linoleic acid is mediated by an intracellular signaling pathway activated by GPR40 that leads to an increase in membrane levels of Cx43 phosphorylated at serine 373 via Akt.
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These data demonstrate that R104 in GPR40 is critically involved in the normal receptor functions. Interestingly, R104P is a registered single-nucleotide polymorphism of GPR40.
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Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4
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results suggest that FFAR1 is the functionally dominant free fatty acid receptor in both human and guinea pig airway smooth muscle.
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upregulation of GPR40 expression enhances the mitogenic response to epoxyeicosatrienoic acids
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Palmitic acid boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase.
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knocking down the expression of the regulatory subunit PKAR1alpha, thereby reproducing the effects of IL-1beta and PGE on VSMCs, we demonstrated the contribution of PKA activity to the observed behavior of VSMCs
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These results suggest that distinct effects of GPR120 and GPR40 are involved in the acquisition of malignant property in pancreatic cancer cells.
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GPR40 functions via both G protein-mediated and beta-arrestin-mediated mechanisms; endogenous and synthetic ligands differentially engage these pathways to promote insulin secretion.
