The Prostanoid EP4 Receptor and Its Signaling Pathway

The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin E₂. It belongs to the family of G protein–coupled receptors. It was originally identified, similar to the EP2 receptor as a G_sα-coupled, adenylyl cyclase–stimulating receptor. EP4 signaling plays a variety of roles through cAMP effectors, i.e., protein kinase A and exchange protein activated by cAMP. However, emerging evidence from studies using pharmacological approaches and genetically modified mice suggests that EP4, unlike EP2, can also be coupled to G_iα, phosphatidylinositol 3-kinase, β-arrestin, or β-catenin. These signaling pathways constitute unique roles for the EP4 receptor. EP4 is widely distributed in the body and thus plays various physiologic and pathophysiologic roles. In particular, EP4 signaling is closely related to carcinogenesis, cardiac hypertrophy, vasodilation, vascular remodeling, bone remodeling, gastrointestinal homeostasis, renal function, and female reproductive function. In addition to the classic anti-inflammatory action of EP4 on mononuclear cells and T cells, recent evidence has shown that EP4 signaling contributes to proinflammatory action as well. The aim of this review is to present current findings on the biologic functions of the EP4 receptor. In particular, we will discuss its diversity from the standpoint of EP4-mediated signaling.