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Gene Review

Ptger4  -  prostaglandin E receptor 4 (subtype EP4)

Mus musculus

Synonyms: EP4, PGE receptor EP4 subtype, PGE2 receptor EP4 subtype, Prostaglandin E2 receptor EP4 subtype, Prostanoid EP4 receptor, ...
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Disease relevance of Ptger4


High impact information on Ptger4


Chemical compound and disease context of Ptger4


Biological context of Ptger4

  • We conclude that EP4 maintains intestinal homeostasis by keeping mucosal integrity and downregulating immune response [1].
  • Promoter analyses of the EP4 receptor gene promoter in RAW 264.7 cells indicated that there is a constitutive negative regulatory region between -992 and -928 bp, a constitutive positive region between -928 and -554 bp, and an LPS/serum-responsive region between -554 and -116 bp [11].
  • To study expression of the EP4 receptor we isolated the mouse EP4 receptor gene; the gene is 10 kilobase pairs (kb) in length and, like other known prostanoid receptor genes, contains three exons and two introns [11].
  • Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice [12].
  • However, 9 h after hCG injection, just before ovulation, the signals for EP4 mRNA were still detectable in both cell types, whereas those for EP2 mRNA were found only in cumulus cells [13].

Anatomical context of Ptger4


Associations of Ptger4 with chemical compounds

  • Prostanoid receptors of murine NIH 3T3 and RAW 264.7 cells. Structure and expression of the murine prostaglandin EP4 receptor gene [11].
  • The response to endogenous PGE2 was blunted in EP4-receptor-deficient mice only and especially after prolonged incubation [17].
  • Similar expression patterns of EP3 and EP4 in the Day 4 pseudopregnant mouse uterus or in the ovariectomized uterus under combined treatment with estrogen and progesterone suggest that these genes are regulated by ovarian steroids rather than by the embryo during the preimplantation period (Days 1-4) [18].
  • Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide [19].
  • The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice [12].
  • Whereas treatment with PGE(2) or the EP4 selective agonists PGE(1)-OH and ONO-AE1-329 induced migration, tubulogenesis, ERK activation and cAMP production in control adenovirus-transduced endothelial EP4(flox/flox) cells, no effects were seen in adenoCre-transduced EP4(flox/flox) cells [20].

Physical interactions of Ptger4

  • Among them, EP2 and EP4 couple to Gs and EP3 to Gi [21].
  • High levels of expression of functional EP4 receptors coupled with Gs-protein was confirmed in C3L5 cells by biochemical assay showing a dose-dependent increase of intracellular cAMP synthesis in response to PGE2 [22].

Regulatory relationships of Ptger4

  • Intracellular TNF-alpha staining was inhibited 20% by EP4/2 agonists [23].
  • Furthermore, EP4 RA suppressed OC formation and prevented the increase in receptor activator of nuclear factor kappaB ligand (RANKL) mRNA levels in the cocultures [16].
  • These results indicate that PGE2 enhances osteoclast formation through its EP4 subtype on osteoblasts [19].
  • In contrast, the EP4 agonist (PGE1-OH) stimulated macrophage MMP-9 expression, which was inhibited by the EP4 antagonist ONO-AE3-208 [24].
  • Alkaline phosphatase-positive nodule formation in the absence or presence of XT-611 was inhibited by an antagonist of EP4 receptor, AH23848B, and synergistically potentiated by 11-deoxy-PGE1, but it was not influenced by other EP antagonists and agonists examined [25].

Other interactions of Ptger4

  • There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways [14].
  • In conclusion, our data indicate that LPS activates airway epithelial TLR4 to cause release of PGE(2) and subsequent EP2 and EP4 receptor-dependent smooth muscle relaxation [26].
  • We have investigated the role of COX-2, EP2 receptor, and EP4 receptor in marrow cells for osteoclastogenesis in cocultures of cancer cells and bone marrow cells [16].
  • TNF-alpha production was inhibited 50-70% at 2-24 h by EP4/2 agonists, whereas IL-6 was enhanced up to approximately 220% [23].
  • Because EP4RA partially inhibited osteoclastogenesis not only in response to PGE(2) but also in response to 1,25D and PTH, these results suggest that activation of the EP4 receptor may play a general role in osteoclastic bone resorption [8].

Analytical, diagnostic and therapeutic context of Ptger4

  • DNA microarray analysis revealed elevated expression of genes associated with immune response and reduced expression of genes with mucosal repair and remodeling in the colon of EP4-deficient mice [1].
  • In addition, an EP4 receptor antagonist (EP4 RA) was added in some cocultures [16].
  • In situ hybridization (ISH) showed that EP4 messenger RNA (mRNA) was expressed on osteoblastic cells but not on multinucleated cells (MNCs) in w/t mice [19].
  • Finally, Western blot analysis of the levels of the EP4 receptor protein in control vs. NS-398-treated cells revealed an induction in protein levels in these cells, correlating with the induction in EP4 mRNA [27].
  • Using a semiquantitative titration analysis method, we show that following the addition of the COX-2-specific inhibitor NS-398, E-prostanoid receptor subtype (EP3 and EP4) mRNA expression was found to increase threefold each vs. the vehicle-treated control [27].


  1. The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. Kabashima, K., Saji, T., Murata, T., Nagamachi, M., Matsuoka, T., Segi, E., Tsuboi, K., Sugimoto, Y., Kobayashi, T., Miyachi, Y., Ichikawa, A., Narumiya, S. J. Clin. Invest. (2002) [Pubmed]
  2. The role of prostaglandin E2 receptors in the pathogenesis of rheumatoid arthritis. McCoy, J.M., Wicks, J.R., Audoly, L.P. J. Clin. Invest. (2002) [Pubmed]
  3. Prostaglandin E receptor EP4 antagonism inhibits breast cancer metastasis. Ma, X., Kundu, N., Rifat, S., Walser, T., Fulton, A.M. Cancer Res. (2006) [Pubmed]
  4. Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice. Miyaura, C., Inada, M., Suzawa, T., Sugimoto, Y., Ushikubi, F., Ichikawa, A., Narumiya, S., Suda, T. J. Biol. Chem. (2000) [Pubmed]
  5. Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4. Hatae, N., Kita, A., Tanaka, S., Sugimoto, Y., Ichikawa, A. J. Biol. Chem. (2003) [Pubmed]
  6. Prostaglandin E2-EP4 signaling initiates skin immune responses by promoting migration and maturation of Langerhans cells. Kabashima, K., Sakata, D., Nagamachi, M., Miyachi, Y., Inaba, K., Narumiya, S. Nat. Med. (2003) [Pubmed]
  7. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nguyen, M., Camenisch, T., Snouwaert, J.N., Hicks, E., Coffman, T.M., Anderson, P.A., Malouf, N.N., Koller, B.H. Nature (1997) [Pubmed]
  8. Effects of selective prostaglandin EP4 receptor antagonist on osteoclast formation and bone resorption in vitro. Tomita, M., Li, X., Okada, Y., Woodiel, F.N., Young, R.N., Pilbeam, C.C., Raisz, L.G. Bone (2002) [Pubmed]
  9. A prostaglandin E2 receptor subtype EP4 agonist attenuates cardiovascular depression in endotoxin shock by inhibiting inflammatory cytokines and nitric oxide production. Sakamoto, A., Matsumura, J., Mii, S., Gotoh, Y., Ogawa, R. Shock (2004) [Pubmed]
  10. Impaired bone resorption by lipopolysaccharide in vivo in mice deficient in the prostaglandin E receptor EP4 subtype. Sakuma, Y., Tanaka, K., Suda, M., Komatsu, Y., Yasoda, A., Miura, M., Ozasa, A., Narumiya, S., Sugimoto, Y., Ichikawa, A., Ushikubi, F., Nakao, K. Infect. Immun. (2000) [Pubmed]
  11. Prostanoid receptors of murine NIH 3T3 and RAW 264.7 cells. Structure and expression of the murine prostaglandin EP4 receptor gene. Arakawa, T., Laneuville, O., Miller, C.A., Lakkides, K.M., Wingerd, B.A., DeWitt, D.L., Smith, W.L. J. Biol. Chem. (1996) [Pubmed]
  12. Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome. Nüsing, R.M., Treude, A., Weissenberger, C., Jensen, B., Bek, M., Wagner, C., Narumiya, S., Seyberth, H.W. J. Am. Soc. Nephrol. (2005) [Pubmed]
  13. Expression of messenger RNA for prostaglandin E receptor subtypes EP4/EP2 and cyclooxygenase isozymes in mouse periovulatory follicles and oviducts during superovulation. Segi, E., Haraguchi, K., Sugimoto, Y., Tsuji, M., Tsunekawa, H., Tamba, S., Tsuboi, K., Tanaka, S., Ichikawa, A. Biol. Reprod. (2003) [Pubmed]
  14. Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse. Nataraj, C., Thomas, D.W., Tilley, S.L., Nguyen, M.T., Mannon, R., Koller, B.H., Coffman, T.M. J. Clin. Invest. (2001) [Pubmed]
  15. Regulation of TNFalpha and interleukin-10 production by prostaglandins I(2) and E(2): studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Shinomiya, S., Naraba, H., Ueno, A., Utsunomiya, I., Maruyama, T., Ohuchida, S., Ushikubi, F., Yuki, K., Narumiya, S., Sugimoto, Y., Ichikawa, A., Oh-ishi, S. Biochem. Pharmacol. (2001) [Pubmed]
  16. The effect of deletion of cyclooxygenase-2, prostaglandin receptor EP2, or EP4 in bone marrow cells on osteoclasts induced by mouse mammary cancer cell lines. Ono, K., Akatsu, T., Kugai, N., Pilbeam, C.C., Raisz, L.G. Bone (2003) [Pubmed]
  17. Contribution of the two Gs-coupled PGE2-receptors EP2-receptor and EP4-receptor to the inhibition by PGE2 of the LPS-induced TNFalpha-formation in Kupffer cells from EP2-or EP4-receptor-deficient mice. Pivotal role for the EP4-receptor in wild type Kupffer cells. Fennekohl, A., Sugimoto, Y., Segi, E., Maruyama, T., Ichikawa, A., Püschel, G.P. J. Hepatol. (2002) [Pubmed]
  18. Potential sites of prostaglandin actions in the periimplantation mouse uterus: differential expression and regulation of prostaglandin receptor genes. Yang, Z.M., Das, S.K., Wang, J., Sugimoto, Y., Ichikawa, A., Dey, S.K. Biol. Reprod. (1997) [Pubmed]
  19. Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide. Sakuma, Y., Tanaka, K., Suda, M., Yasoda, A., Natsui, K., Tanaka, I., Ushikubi, F., Narumiya, S., Segi, E., Sugimoto, Y., Ichikawa, A., Nakao, K. J. Bone Miner. Res. (2000) [Pubmed]
  20. Prostaglandin E2-EP4 receptor promotes endothelial cell migration via ERK activation and angiogenesis in vivo. Rao, R., Redha, R., Macias-Perez, I., Su, Y., Hao, C., Zent, R., Breyer, M.D., Pozzi, A. J. Biol. Chem. (2007) [Pubmed]
  21. Functional domains essential for Gs activity in prostaglandin EP2 and EP3 receptors. Sugimoto, Y., Nakato, T., Kita, A., Hatae, N., Tabata, H., Tanaka, S., Ichikawa, A. Life Sci. (2003) [Pubmed]
  22. Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells. Timoshenko, A.V., Xu, G., Chakrabarti, S., Lala, P.K., Chakraborty, C. Exp. Cell Res. (2003) [Pubmed]
  23. Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-alpha and IL-6 production. Akaogi, J., Yamada, H., Kuroda, Y., Nacionales, D.C., Reeves, W.H., Satoh, M. J. Leukoc. Biol. (2004) [Pubmed]
  24. Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages. Pavlovic, S., Du, B., Sakamoto, K., Khan, K.M., Natarajan, C., Breyer, R.M., Dannenberg, A.J., Falcone, D.J. J. Biol. Chem. (2006) [Pubmed]
  25. Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. Miyamoto, K., Suzuki, H., Yamamoto, S., Saitoh, Y., Ochiai, E., Moritani, S., Yokogawa, K., Waki, Y., Kasugai, S., Sawanishi, H., Yamagami, H. J. Bone Miner. Res. (2003) [Pubmed]
  26. Lipopolysaccharide Induces Epithelium- and Prostaglandin E2-Dependent Relaxation of Mouse Isolated Trachea through Activation of Cyclooxygenase (COX)-1 and COX-2. Balzary, R.W., Cocks, T.M. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  27. Effect of COX-2 inhibitor NS-398 on expression of PGE2 receptor subtypes in M-1 mouse CCD cells. Nasrallah, R., Laneuville, O., Ferguson, S., Hébert, R.L. Am. J. Physiol. Renal Physiol. (2001) [Pubmed]
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