title: Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands.
abstract: 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. The DP receptor-cognate ligand, prostaglandin D2(PGD2) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor-cognate ligand, prostaglandin E2(PGE2) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation. However, since PGD2and/or PGE2activate DP and EP2 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 an in silico simulation to predict binding patterns among DP or EP2 receptors and PGD2, PGE2, or prostaglandin F2αas the reference prostanoid, that DP and EP2 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 the DP receptors to the noncognate ligands were approximately 10 times lower than those of EP2 receptors. Thus, EP2 receptors seem to be able to distinguish endogenous ligands better than DP receptors, thereby both receptors are plausibly gaining role-sharing functions with respect to one another as the copies of duplicated gene.
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Suganami
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.|Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences & Institute of Biomedical Sciences, Graduate School, Tokushima University, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Fujino
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: Iori
authors.initials: I
authors.lastname: Okura
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yanagisawa
authors.affiliation: Bio-IT R&D Office, Fujitsu Limited, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Regan
authors.affiliation: Department of Bioinformatics, Graduate School of Medicine, Chiba University, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
mesh_terms: D000595:Amino Acid Sequence; D001667:Binding, Competitive; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D015237:Dinoprost / Q000737:chemistry / Q000378:metabolism; D015232:Dinoprostone / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D015230:Prostaglandin D2 / Q000737:chemistry / Q000378:metabolism*; D000072417:Protein Domains; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D008024:Ligands; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015237:Dinoprost; D000242:Cyclic AMP; D015232:Dinoprostone; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
keywords: CH-π bonds; DP receptors; EP2 receptors; biased ligands; prostanoids