The inflammatory mediator prostaglandin E₂ (PGE₂) binds to G_s-coupled EP2 and EP4 receptors. These receptors are located in the locus coeruleus (LC), the principal noradrenergic nucleus in the brain, but their functional role remains unknown. In this study, the PGE₂ EP2 and EP4 receptors in LC cells from male rat brain slices were pharmacologically characterized by single-unit extracellular electrophysiology. The EP2 receptor agonists butaprost (0.01-10 μM) and treprostinil (0.03-10 µM) and the EP4 receptor agonists rivenprost (0.01 nM-1 µM) and TCS2510 (0.20 nM-2 µM) increased the firing rate of LC neurons in a concentration-dependent manner. The EP2 receptor antagonist PF-04418948 (10 nM) hindered the excitatory effect of butaprost and treprostinil while the EP4 receptor antagonist L-161,982 (30 and 300 nM) blocked the excitatory effect caused by rivenprost and TCS2510. The effects of butaprost and rivenprost were prevented by extracellular sodium replacement but were not modified by the protein kinase A (PKA) activator 8-Br-cAMP (1 mM) or the inhibitor H-89 (10 μM). However, the G_βγ subunit blocker gallein (20 μM) hindered the stimulatory effect of butaprost while the G_αs subunit inhibitor NF449 (10 µM) prevented that of rivenprost. Finally, rivenprost-induced stimulation (30 nM) was not occluded by butaprost (1 µM). In conclusion, activation of EP2 and EP4 receptors excites LC noradrenergic neurons through sodium-dependent currents via different G protein subunits in male rat brain slices. EP2 and EP4 in the LC may constitute pharmacological targets for the treatment of pain, fever, drug addiction, anxiety and neuroinflammatory diseases.

01 Nov 2024·Biomedicine & Pharmacotherapy

Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production

Article

Author: Föller, Michael ; Hammerschmidt, Katharina ; Feger, Martina ; Rausch, Steffen ; Alber, Jana ; Liesche, Ilona

Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E₂ (PGE₂) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE₂ and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE₂ and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE₂ signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE₂ signaling, this effect is likely of clinical relevance.

01 Oct 2024·Prostaglandins & Other Lipid Mediators

Effect of PGE2 on TT cells viability and division

Article

Author: Lu, Chien-Chen

Previous studies have shown prostaglandin E2 (PGE2) produced a marked increase in calcitonin secretion in human C-cells derived from medullary thyroid carcinoma. However, it's unclear whether PGE2 can increase the growth of C cells. In this study, we use TT cells as a C cell model to investigate the effect of PGE2 on the growth of C cells. The results revealed that both PGE2 and arachidonic acid (AA) significantly increased the count of TT cells, whereas indomethacin and Dup697 reduced this count. Notably, an increase in the level of AA was associated with an increase in the number of proliferating TT cells, indicating a dose-response relationship. PGE2 and its receptor agonists (sulprostone and butaprost) enhanced the proliferation of TT cells. By contrast, 17-phenyl-trinor-PGE2 exerted no significant effect on TT cell proliferation, whereas L161982 suppressed it. The positive effect of AA on TT cell proliferation was inhibited by indomethacin, NS398, Dup697 (complete inhibition), and SC560. Both PGE2 and AA increased the level of p-STAT5a. The positive effect of AA on p-STAT5a was completely inhibited by Dup697 but not indomethacin, NS398, or SC560. Treatment with indomethacin or Dup697 alone reduced the level of STAT5a in TT cells. AA increased the level of STAT5a, but this effect was inhibited by indomethacin, NS398, and Dup697. Overall, this study confirms the effect of PGE2 on the proliferation of TT cells. This effect is likely mediated through EP2, EP3, and EP4 receptors and associated with an increase in p-STAT5a level within TT cells.

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