Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

Mena, Sandra Jaqueline; Manosalva, Carolina; Carretta, María Daniella; Teuber, Stefanie; Olmo, Iván del; Burgos, Rafael A.; Hidalgo, María A.

doi:10.1177/1753425916656765

Cited by 28 publications

(47 citation statements)

References 57 publications

(94 reference statements)

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“…Additionally, EET regulation of Cx43 and COX-2 requires ERK phosphorylation (11,12). Activation of GPR40 also stimulates ERK phosphorylation in several cell types (38,51,52). We observed that the GPR40 antagonist GW1100 and GPR40 targeted siRNA and the MEK inhibitor U0126 blocked 11,12-EET-induced ERK phosphorylation in HUVECs.…”

Section: Discussionmentioning

confidence: 52%

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GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC 50 = 0.58 ± 0.08 µM, 0.91 ± 0.08 µM, 3.9 ± 0.06 µM and 19 ± 0.37 nM, respectively). EETs with cisand trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12-and 14,15-vicdihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET-and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAP kinase inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EETinduced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation. INTRODUCTIONhttp://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 52%

“…In neutrophils, activators of GPR40 increase COX-2 expression by decreasing the endogenous NFκB inhibitor IκB (51). The increase in COX-2 and decrease in IκB were blocked by GW1100 and inhibitors of MEK.…”

Section: Discussionmentioning

confidence: 96%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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“…Several studies have revealed that in breast cancer cell lines, the ERK1/2 and PI3K pathways are involved in proliferation; in part via FFA1 [29]. In addition, numerous observations suggested FFA1/ERK1/2 activation exhibited anti-apoptotic function [30], supported neuronal survival [10] and memory, induced osteocyte apoptosis [31] and had anti-inflammatory effects such as granule release and gene expression in neutrophils [32]. As a consequence, there is significant interest in understanding ERK1/2 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…There is growing evidence indicating that the FFA1 downstream ERK1/2 signal pathway participates in the regulation of various physiological functions [10, 30–32]. For better understanding of the specific mechanism of FFA1-mediated ERK1/2 activation, we examined the time course of ERK1/2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Agonist-induced activation of human FFA1 receptor signals to extracellular signal-regulated kinase 1 and 2 through Gq- and Gi-coupled signaling cascades

Qian

Chun

et al. 2017

Cell Mol Biol Lett

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BackgroundFFA1 is abundantly expressed in the liver, skeletal muscle, monocytes and nervous system, but is particularly abundant in pancreatic β cells. It is widely believed that FFA1 exerts its regulatory roles in a variety of physiological and pathological functions. In response to oleic acid, FFA1 has been shown to induce the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) through a mechanism involving EGFR transactivation in a breast cancer cell line. However, the underlying molecular mechanism for ERK1/2 activation mediated by n-6 free fatty acid (LA) in HEK293 cells remains to be further elucidated.MethodsA FLAG-FFA1 vector was stably expressed in HEK293 cells. Western blot analysis was applied to investigate the change in LA-induced ERK1/2 phosphorylation change in response to kinase inhibitors. Arrestin-2/3-specific siRNA was used to analyze the effect of arrestin-2/3 knockdown on FFA1-mediated ERK1/2 activation.ResultsWe proved that activation of ERK1/2 by LA was rapid, peaking at 5 min. Further experiments proved that FFA1 couples to a Gq protein and activates PI-PLC, which induces the IP3/Ca2+ and DAG/PKC signal pathways, both of which are involved in ERK1/2 activation. We also showed that there is no EGFR transactivation, arrestin-2/3 or Gβγ pathway participation in ERK1/2 phosphorylation. Treating cells with PTX abolished ERK1/2 activation at a late time point (≥20 min), indicating a critical role for Gi subunits in FFA1-mediated ERK1/2 activation.ConclusionsOur study provides a detailed delineation of the LA-mediated activation of ERK1/2 in HEK293 cells that are stably transfected with human FFA1. We also present evidence of Gi/Gq-induced synergism in the regulation of ERK1/2 phosphorylation. These observations may provide new insights into the pharmacological effects of FFA1 and the physiological functions modulated by FFA1-mediated activation of ERK1/2.Electronic supplementary materialThe online version of this article (doi:10.1186/s11658-017-0043-3) contains supplementary material, which is available to authorized users.

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“…Rapid recruitment of neutrophils and efficient chemotaxis to sites of infection are essential preludes to neutrophil function and clearance of bacteria. Intriguingly, GW9508 treatment can induce IL-8 release from bovine neutrophils ( 22 ). This chemokine is a powerful attractant for both neutrophils and monocytes and may explain why higher numbers of these leukocytes are recruited to the peritoneal cavity following GW9508 administration ( Figure 3 ) in a feed-forward mechanism.…”

Section: Discussionmentioning

confidence: 99%

The GPR40 Agonist GW9508 Enhances Neutrophil Function to Aid Bacterial Clearance During E. coli Infections

et al. 2020

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G-protein-coupled receptor 40 (GPR40) is known to play a role in the regulation of fatty acids, insulin secretion, and inflammation. However, the function of this receptor in human neutrophils, one of the first leukocytes to arrive at the site of infection, remains to be fully elucidated. In the present study, we demonstrate that GPR40 is upregulated on activated human neutrophils and investigated the functional effects upon treatment with a selective agonist; GW9508. Interestingly, GPR40 expression was up-regulated after neutrophil stimulation with platelet-activating factor (10 nM) or leukotriene B 4 (LTB 4 , 10 nM) suggesting potential regulatory roles for this receptor during inflammation. Indeed, GW9508 (1 and 10 μM) increased neutrophil chemotaxis in response to the chemokine IL-8 (30 ng/ml) and enhanced phagocytosis of Escherichia coli by approximately 50% when tested at 0.1 and 1 μM. These results were translated in vivo whereby administration of GW9508 (10 mg/kg, i.p.) during E. coli infections resulted in elevated peritoneal leukocyte infiltration with a higher phagocytic capacity. Importantly, GW9508 administration also modulated the lipid mediator profile, with increased levels of the pro-resolving mediators resolvin D3 and lipoxins. In conclusion, GPR40 is expressed by activated neutrophils and plays an important host protective role to aid clearance of bacterial infections.

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Differential free fatty acid receptor-1 (FFAR1/GPR40) signalling is associated with gene expression or gelatinase granule release in bovine neutrophils

Cited by 28 publications

References 57 publications

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Agonist-induced activation of human FFA1 receptor signals to extracellular signal-regulated kinase 1 and 2 through Gq- and Gi-coupled signaling cascades

The GPR40 Agonist GW9508 Enhances Neutrophil Function to Aid Bacterial Clearance During E. coli Infections

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