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

Background Human DP and EP2 receptors are two of the most homologically related receptors coupling with G(alpha)s-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 beta 1- and beta 2-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) D-2 or PGE(2) 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 PGD(2)/EP2 receptors exerted a greater effect on PDE4 activity than PGE(2)/EP2 receptors. Moreover, by MD analysis, either the PGD(2) or EP2 receptor was moved and the distance was shortened between them. According to the results, DP receptors retain reactivity for PGE(2), but EP2 receptors may be activated only by PGE(2), at least in terms of cAMP formation, through the differential functional coupling of PDE4 probably with beta-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, PGD(2).