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

Abstract

Prostaglandin E2 (PGE2) is well-known as an endogenous pro-inflammatory 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.

The Gαs‐protein‐mediated pathway may be steadily stimulated by prostanoid EP2 receptors, but not by EP4 receptors

“…Cell culture and materials HEK-EP2 cells or HEK-EP4 cells [11] were cultured in Dulbecco's modified Eagle's medium (DMEM; Nacalai Tesque, Kyoto, Japan) containing 10% FBS (Thermo Fisher Scientific, Waltham, MA, USA), 250 μgÁmL −1 of geneticin (Phyto Technology Laboratories, Shawnee Mission, KA, USA), 200 μgÁmL −1 of hygromycin B (Enzo Life Science, Farmingdale, NY, USA), and 100 μgÁmL −1 of gentamicin (Life Technologies, Carlsbad, CA, USA) at 37 °C. PGE 2 was obtained from Cayman Chemical (Ann Arbor, MI, USA).…”

“…Recently, 15‐keto‐PGE 2 , a metabolite of PGE 2 , was reported to act as a switch for cellular signaling to the EP2 receptor‐mediated pathway from the EP4 receptor‐mediated pathway [ 11 ]. Thus, PGE 2 ‐initiated EP4 receptor‐mediated signaling may be terminated by the subsequent 15‐keto‐PGE 2 ‐adopted EP2 receptor‐mediated signaling if both receptors are expressed on nearby tissues/cells.…”

Natural Compounds as Guides for the Discovery of Drugs Targeting G-Protein-Coupled Receptors

“…On the one hand, very complex structures that are phlorotannins, isolated from Eisenia bicyclis and Ecklonia cava, behave as agonists of dopamine receptors and may contribute to reduce the toxic effect of a compound, 1-methyl-4-phenylpyridinium (MPP + ), used for the development of Parkinson's disease animal models [17,21]. On the other hand, Gracilaria verrucose produces a high number of prostaglandins (PGs) such as PGA 2 , PGE 2 , PGF 2 , and 15-keto-PGE 2 , (some of which have the same chemical structures as mammalian PGs) that are able to interact with prostanoid receptors [18,22,23].…”

Why PGD2 has different functions from PGE2

“…We recently reported that a metabolite of PGE 2 , 15‐keto‐PGE 2 may have an additional role as a biased/partial agonist to take over the actions of PGE 2 to gradually terminate reactions through the EP2 and EP4 receptors. [ 39 ] Although 15‐keto‐PGE 2 is regarded as an inactive metabolite of PGE 2 , it functions as a “switched agonist” for cellular signaling from the EP4 receptor‐mediated pathway to the EP2 receptor‐mediated pathway, thereby restoring/terminating inflammatory reaction and/or maintaining homeostasis, such as in colorectal tissues/cells functions. [ 39 ] Endogenous PGD 2 and/or PGE 2 may function as biased ligands to exert opposing functions through the same receptors.…”

“…[ 39 ] Although 15‐keto‐PGE 2 is regarded as an inactive metabolite of PGE 2 , it functions as a “switched agonist” for cellular signaling from the EP4 receptor‐mediated pathway to the EP2 receptor‐mediated pathway, thereby restoring/terminating inflammatory reaction and/or maintaining homeostasis, such as in colorectal tissues/cells functions. [ 39 ] Endogenous PGD 2 and/or PGE 2 may function as biased ligands to exert opposing functions through the same receptors. Since the amount of endogenous prostanoids, including their metabolites, is vast, if these biased mechanisms are elucidated in more detail and properly utilized, prostanoids have potential as useful endogenous biased ligands and/or as leading compounds for the development of novel therapeutics in the future.…”