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

作者：Suzu Endo, Akiko Suganami, Keijo Fukushima, Kanaho Senoo, Yumi Araki, John W. Regan, Masato Mashimo, Yutaka Tamura, Hiromichi Fujino · 发表于：Journal of Biological Chemistry · 年份：2020 · DOI：10.1074/jbc.ra120.013988 · 被引用次数：21 · 研究领域：Inflammatory mediators and NSAID effects、Estrogen and related hormone effects、Eicosanoids and Hypertension Pharmacology

Prostaglandin E 2 (PGE 2 ) 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 PGE 2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gα s -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 PGE 2 , it is metabolized to 15-keto-PGE 2 . Thus, 15-keto-PGE 2 has long been considered an inactive metabolite of PGE 2 . However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE 2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE 2 -activated EP4 receptor–mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE 2 –activated EP2 receptor–mediated signaling after PGE 2 is metabolized to 15-keto-PGE 2 . The present results shed light on new aspects of 15-keto-PGE 2 , which may have important roles in passing on activities to EP2 receptors from PGE 2 -stimulated EP4 receptors as a "switched agonist." This novel mechanism may be significant for gradually terminating PGE 2 -evoked inflamm...