Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands

Akiko Suganami, Hiromichi Fujino, Iori Okura, Naoki Yanagisawa, Hajime Sugiyama, John W. Regan, Yutaka Tamura, Toshihiko Murayama

Research output: Contribution to journalArticle

2 Scopus citations

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 PGD2 and/or PGE2 activate 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 F as 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.

Original languageEnglish (US)
Pages (from-to)3931-3940
Number of pages10
JournalFEBS Journal
Volume283
Issue number21
DOIs
StatePublished - Nov 1 2016

Keywords

  • CH-π bonds
  • DP receptors
  • EP2 receptors
  • biased ligands
  • prostanoids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Suganami, A., Fujino, H., Okura, I., Yanagisawa, N., Sugiyama, H., Regan, J. W., Tamura, Y., & Murayama, T. (2016). Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands. FEBS Journal, 283(21), 3931-3940. https://doi.org/10.1111/febs.13899