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

Abstract

EP2 and EP4 prostanoid receptors have long been considered to have similar roles, since they are known to couple with Gαs‐protein and activate cAMP‐mediated signaling pathways. In this study, we re‐evaluated the results of cAMP assays with or without phosphodiesterase (PDE) inhibitor pretreatment. Here, we show that in the absence of PDE 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. Thus, EP2 and EP4 receptors may not be similar Gαs‐coupled receptors but instead substantially different receptors with distinct roles.

Prostanoid receptors in hyperfiltration‐mediated glomerular injury: Novel agonists and antagonists reveal opposing roles for EP2 and EP4 receptors

“…Figure S2 shows that EP2 and EP4 agonists and antagonists induce opposite effects on phosphorylation of Akt and β‐catenin, but not GSK3β. EP2 and EP4 are membrane‐localized GPCRs that share 30% homology and activate adenylate cyclase, but may have very distinct roles and different downstream signaling 53 . For example, resting peritoneal macrophages C3H/HeN express only EP4.…”

“…EP2 and EP4 are membrane-localized GPCRs that share 30% homology and activate adenylate cyclase, but may have very distinct roles and different downstream signaling. 53 For example, resting peritoneal macrophages C3H/HeN express only EP4. While stimulation of these cells by LPS without indomethacin induces EP2 and downregulates EP4 expression but LPS with indomethacin upregulates EP4.…”