15-Keto-PGE₂はPGE₂によるシグナルを抑制するバイアスアゴニストとして作用する

抄録

E type prostanoid (EP) receptors are cognates for prostaglandin E₂ 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. Additionally, we show that in the absence of phosphodiesterase inhibitor pretreatment, prostaglandin E₂ causes accumulation of cAMP in EP2 receptors, whereas markedly low levels of cAMP accumulated in EP4 receptors. By applying the Black/Leff operational model calculation, we found that EP2 receptors have a biased ability to intrinsically activate the Gαs-protein-mediated pathway, whereas EP4 receptors have strong biased activity for the Gαi-protein-mediated pathway. 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.”