Metabolite G-protein coupled receptor signaling: Potential regulation of eicosanoids

Tang, Xiao; Hou, Yaolin; Schwartz, Thue W.; Haeggström, Jesper Z.

doi:10.1016/j.bcp.2022.115208

Cited by 6 publications

(4 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, AA can be metabolized by the enzyme 5-lipoxygenase (5-LOX) to generate LTs. 5-LOX interacts with 5-lipoxygenase activating protein (FLAP) and converts AA to LTA4 [10]. Therefore, LTs biosynthesis is highly dependent on the activities of cPLA2 and 5-LOX.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, phosphorylation at Ser523 residue by PKA suppresses 5-LOX activity [13]. The G-protein coupled receptors (GPCRs) can sense extracellular metabolites and thus regulate inflammatory responses, including eicosanoid production [10]. Signaling triggered by GPCRs includes calcium mobilization and the activation of several downstream kinases, such as ERKs, p38MAPK, and p38MAPK-regulated MAPKAPK, which in turn can regulate cPLA2 and 5-LOX activity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase

Pecchillo Cimmino,

Panico,

Scarano

et al. 2024

Antioxidants

View full text Add to dashboard Cite

Phospholipases (PL) A2 catalyzes the hydrolysis of membrane phospholipids and mostly generates arachidonic acid (AA). The enzyme 5-lipoxygenase (5-LOX) can metabolize AA to obtain inflammatory leukotrienes, whose biosynthesis highly depends on cPLA2 and 5-LOX activities. Formyl Peptide Receptor 2 (FPR2) belongs to a subfamily of class A GPCRs and is considered the most versatile FPRs isoform. Signaling triggered by FPR2 includes the activation of several downstream kinases and NADPH oxidase (NOX)-dependent ROS generation. In a metabolomic analysis we observed a significant increase in AA concentration in FPR2-stimulated lung cancer cell line CaLu-6. We analyzed cPLA2 phosphorylation and observed a time-dependent increase in cPLA2 Ser505 phosphorylation in FPR2-stimulated cells, which was prevented by the MEK inhibitor (PD098059) and the p38MAPK inhibitor (SB203580) and by blocking NOX function. Similarly, we demonstrated that phosphorylation of 5-LOX at Ser271 and Ser663 residues requires FPR2-dependent p38MAPK and ERKs activation. Moreover, we showed that 5-LOX Ser271 phosphorylation depends on a functional NOX expression. Our overall data demonstrate for the first time that FPR2-induced ERK- and p38MAPK-dependent phosphorylation/activation of cPLA2 and 5-LOX requires a functional NADPH oxidase. These findings represent an important step towards future novel therapeutic possibilities aimed at resolving the inflammatory processes underlying many human diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase

Pecchillo Cimmino,

Panico,

Scarano

et al. 2024

Antioxidants

View full text Add to dashboard Cite

show abstract

“…Determining that LPA was a cognate GPCR ligand placed it in a class of other inflammatory lipids that signal through GPCRs including eicosanoids and sphingosine‐1‐phosphate (S1P) 3,21 . These signaling lipids regulate cell‐type specific functions ranging from innate inflammation, hemostasis and angiogenesis and lymphocyte recirculation.…”

Section: Introductionmentioning

confidence: 99%

“…3,[16][17][18][19][20] Determining that LPA was a cognate GPCR ligand placed it in a class of other inflammatory lipids that signal through GPCRs including eicosanoids and sphingosine-1-phosphate (S1P). 3,21 These signaling lipids regulate cell-type specific functions ranging from innate inflammation, hemostasis and angiogenesis and lymphocyte recirculation. Similar to LPA, S1P is also an endogenously produced lysophospholipid and, as extracellular bioactive lipids, both lipids signal to cells via low nM affinity association with cognate GPCRs: six GPCRs for LPA, LPA 1-6 , and five GPCRs for S1P, S1P 1-5 .…”

mentioning

confidence: 99%

Regulation of CD8 T‐cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid

Torres

Turner

D’Antonio

et al. 2023

Immunological Reviews

View full text Add to dashboard Cite

SummaryLysophosphatidic acid (LPA) is an endogenous bioactive lipid that is produced extracellularly and signals to cells via cognate LPA receptors, which are G‐protein coupled receptors (GPCRs). Mature lymphocytes in mice and humans express three LPA receptors, LPA2, LPA5, and LPA6, and work from our group has determined that LPA5 signaling by T lymphocytes inhibits specific antigen‐receptor signaling pathways that ultimately impair lymphocyte activation, proliferation, and function. In this review, we discuss previous and ongoing work characterizing the ability of an LPA‐LPA5 axis to serve as a peripheral immunological tolerance mechanism that restrains adaptive immunity but is subverted during settings of chronic inflammation. Specifically, LPA‐LPA5 signaling is found to regulate effector cytotoxic CD8 T cells by (at least) two mechanisms: (i) regulating the actin‐microtubule cytoskeleton in a manner that impairs immunological synapse formation between an effector CD8 T cell and antigen‐specific target cell, thus directly impairing cytotoxic activity, and (ii) shifting T‐cell metabolism to depend on fatty‐acid oxidation for mitochondrial respiration and reducing metabolic efficiency. The in vivo outcome of LPA5 inhibitory activity impairs CD8 T‐cell killing and tumor immunity in mouse models providing impetus to consider LPA5 antagonism for the treatment of malignancies and chronic infections.

show abstract

Molecular Mechanism of Action of GPR91 Agonists and Antagonists: Insights from Molecular Dynamics Simulation

Zhang,

Lv,

Zhu

et al. 2024

Chem. Res. Chin. Univ.

View full text Add to dashboard Cite

Metabolite G-protein coupled receptor signaling: Potential regulation of eicosanoids

Cited by 6 publications

References 70 publications

Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase

Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase

Regulation of CD8 T‐cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid

Molecular Mechanism of Action of GPR91 Agonists and Antagonists: Insights from Molecular Dynamics Simulation

Contact Info

Product

Resources

About