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 D (PGD ) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor-cognate ligand, prostaglandin E (PGE ) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation. However, since PGD and/or PGE 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 PGD , PGE , 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.

PGE1 and E3 show lower efficacies than E2 to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

“…PGE 3 was previously shown to reduce cellular proliferation in A549 human lung cancer cells [18] and mouse melanoma B16 cells [19]. Moreover, the susceptibilities of DP receptors to PGE 2 or PGF 2a were~10-fold less than that of EP2 receptors to PGD 2 or PGF 2a ; therefore, EP2 receptors appear to recognize differences in endogenous prostanoids better than DP receptors [20]. Although PGE 1 and PGE 3 exhibit anti-cancer activities, research has focused on nutritional aspects, not the effects of PGE 1 and/or PGE 3 but rather those of dihomo-c-linolenic acid and/or EPA.…”

“…As noted above, PGE 2 is recognized as a pro-cancer prostanoid [1][2][3], whereas PGE 1 and PGE 3 function as anti-cancer prostanoids [14,15]. We previously reported that endogenous prostanoids may not serve as alternative or spare ligands for noncognitive prostanoid receptors [20,21]. PGE 3 was previously shown to reduce cellular proliferation in A549 human lung cancer cells [18] and mouse melanoma B16 cells [19].…”

“…Thus, for example, PGE 1 was reported to inhibit the growth of HeLa human cervical cancer cells [16] and to reduce the growth of and invasion by B16-F10 murine melanoma cells [17]. For example, prostaglandin D 2 (PGD 2 ), PGE 2 and prostaglandin F 2a (PGF 2a ) have been shown to preferentially activate TCF/b-cat-mediated signaling over the G as -protein/ cAMP signaling of D-type prostanoid (DP) receptors and EP2 receptors [20]. The anti-cancer cell growth effects of PGE 3 are considered to be mediated in a manner that is independent of the G as -protein/cAMP/protein kinase A (PKA) pathways [15].…”

“…The anti-cancer cell growth effects of PGE 3 are considered to be mediated in a manner that is independent of the G as -protein/cAMP/protein kinase A (PKA) pathways [15]. Accordingly, endogenous prostanoids should not be recognized as cognate or slow-reacting alternate ligands, and all of them are potential endogenous biased ligands [20]. However, because the structures of PGEs closely resemble each other instead of the fatty acids themselves, their metabolite prostanoids, PGE 1 and PGE 3 , have the ability to activate the same receptors, similar to PGE 2 .…”

“…However, because the structures of PGEs closely resemble each other instead of the fatty acids themselves, their metabolite prostanoids, PGE 1 and PGE 3 , have the ability to activate the same receptors, similar to PGE 2 . We previously reported that endogenous prostanoids may not serve as alternative or spare ligands for noncognitive prostanoid receptors [20,21]. For example, prostaglandin D 2 (PGD 2 ), PGE 2 and prostaglandin F 2a (PGF 2a ) have been shown to preferentially activate TCF/b-cat-mediated signaling over the G as -protein/ cAMP signaling of D-type prostanoid (DP) receptors and EP2 receptors [20].…”