15-keto-prostaglandin E2, the metabolite of prostaglandin E2, may work as biased agonist for EP2 and EP4 receptors.

Prostaglandin E2 (PGE2) are known to be involved in inflammation and cancer. There are four subtypes of E-type prostanoid (EP) receptors, EP1 to EP4, for PGE2. Among them, EP2 receptor and EP4 receptor are frequently confused because they are both coupled with Gs-protein. Although, we have previously shown that EP4 receptor is additionally coupled with Gi-protein. PGE2 is metabolized to 15-keto-PGE2 by the action of 15-hydroxy prostaglandin dehydrogenase. 15-keto-PGE2 has been considered as an inactive form of PGE2. However, we thought 15-keto-PGE2 may activate EP receptor subtypes as biased agonist, since the only difference between PGE2 and 15-keto-PGE2 is a hydroxyl or a carbonyl functional group at position 15. Here we found that 15-keto-PGE2 acts as a full agonist for EP2 receptor, while acting as a partial agonist for EP4 receptor. In addition, when compared to the affinity and efficacy, it was found that PGE2 is tend to activate EP4 receptor, but when it is metabolized to 15-keto-PGE2, it prefers to activate EP2 receptor. Thus, 15-keto-PGE2 may not be just an inactive form of PGE2, but may involve in the biological and physiological roles that need to be elucidated.