The differential functional coupling of phosphodiesterase 4 to human DP and EP2 prostanoid receptors stimulated with PGD2 or PGE2

Iori Okura, Nanae Hasuoka, Kanaho Senoo, Akiko Suganami, Keijo Fukushima, John W. Regan, Masato Mashimo, Toshihiko Murayama, Yutaka Tamura, Hiromichi Fujino

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Human DP and EP2 receptors are two of the most homologically related receptors coupling with Gαs-protein, which stimulate adenylyl cyclase to produce cAMP. Indeed, both receptors are considered to be generated by tandem duplication. It has been reported that other highly homologous and closely related β1- and β2-adrenergic receptors interact distinctly with and differentially regulate cAMP-specific phosphodiesterase (PDE) 4 recruitment. Methods: First, we focused on the cAMP degradation pathways of DP and EP2 receptors stimulated by prostaglandin (PG) D2 or PGE2 using HEK cells stably expressing either human DP receptors or EP2 receptors. Then, distances between ligands and amino acids of the receptors were evaluated by molecular dynamics (MD) analysis. Results: We found that PGD2/EP2 receptors exerted a greater effect on PDE4 activity than PGE2/EP2 receptors. Moreover, by MD analysis, either the PGD2 or EP2 receptor was moved and the distance was shortened between them. According to the results, DP receptors retain reactivity for PGE2, but EP2 receptors may be activated only by PGE2, at least in terms of cAMP formation, through the differential functional coupling of PDE4 probably with β-arrestin. Conclusion: Since DP receptors and EP2 receptors are considered to be duplicated genes, DP receptors may still be in a rapid evolutionary stage as a duplicated copy of EP2 receptors and have not yet sufficient selectivity for their cognate ligand, PGD2.

Original languageEnglish (US)
Pages (from-to)946-953
Number of pages8
JournalPharmacological Reports
Volume73
Issue number3
DOIs
StatePublished - Jun 2021

Keywords

  • Human DP receptors
  • Human EP2 receptors
  • PDE4
  • PGD
  • PGE

ASJC Scopus subject areas

  • Pharmacology

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