Human DP and EP 2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Human D‐type prostanoid (DP) and E‐type prostanoid 2 (EP2) receptors are G protein‐coupled receptors and are regarded as the most closely related receptors among prostanoid receptors because they are generated by tandem duplication. TheDPreceptor‐cognate ligand, prostaglandin D2(PGD2) has the ability to activate not onlyDPreceptors but alsoEP2 receptors. Likewise, theEP2 receptor‐cognate ligand, prostaglandin E2(PGE2) has the ability to activateDPreceptors in addition toEPreceptors in order to stimulatecAMPformation. However, sincePGD2and/orPGE2activateDPandEP2 receptors to similar maximal levels, that is, their similar efficacies, differences between the ligands in each receptor have not yet been determined in detail except for their different affinities. Herein we demonstrated, using anin silicosimulation to predict binding patterns amongDPorEP2 receptors andPGD2,PGE2, or prostaglandin F2αas the reference prostanoid, thatDPandEP2 receptors plausibly take on distinct forms depending on the diverse binding of different ligands. Since these ligands have the potential to make these receptors form distinct conformations with discrete signaling pathways, they are consequently regarded as endogenous biased ligands. Moreover, by using functional assays, the susceptibilities of theDPreceptors to the noncognate ligands were approximately 10 times lower than those ofEP2 receptors. Thus,EP2 receptors seem to be able to distinguish endogenous ligands better thanDPreceptors, thereby both receptors are plausibly gaining role‐sharing functions with respect to one another as the copies of duplicated gene.