15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling

Suzu Endo, Akiko Suganami, Keijo Fukushima, Kanaho Senoo, Yumi Araki, John W. Regan, Masato Mashimo, Yutaka Tamura, Hiromichi Fujino

Research output: Contribution to journalArticle

Abstract

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2 Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2 However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor-mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2-activated EP2 receptor-mediated signaling after PGE2 is metabolized to 15-keto-PGE2 The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a "switched agonist." This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions.

Original languageEnglish (US)
Pages (from-to)13338-13352
Number of pages15
JournalThe Journal of biological chemistry
Volume295
Issue number38
DOIs
StatePublished - Sep 18 2020

Keywords

  • 15-keto-PGE2
  • biased agonist
  • biased ligand
  • bioinformatics
  • cancer biology
  • EP2 prostanoid receptors
  • EP4 prostanoid receptors
  • G-protein–coupled receptor (GPCR)
  • PGE2
  • pharmacology
  • prostaglandin
  • Schild regression
  • switched agonist
  • switched ligand

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Endo, S., Suganami, A., Fukushima, K., Senoo, K., Araki, Y., Regan, J. W., Mashimo, M., Tamura, Y., & Fujino, H. (2020). 15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling. The Journal of biological chemistry, 295(38), 13338-13352. https://doi.org/10.1074/jbc.RA120.013988