Disease relevance of Ptger2

• Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis) [1].
• Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice [1].
• The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia [2].
• In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures [3].
• In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation [3].

High impact information on Ptger2

• To evaluate the physiologic role of the PGE2 EP2 receptor subtype, we created mice with targeted disruption of this gene (EP2-/-) [4].
• When fed a diet high in salt, the EP2-/- mice developed profound systolic hypertension, whereas wild-type mice showed no change in systolic blood pressure [4].
• EP2-/- mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure [4].
• Analysis of wild-type and EP2-/- mice on day 5 of pregnancy indicated that the reduced litter size of EP2-/- mice is due to a pre-implantation defect [4].
• However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 [5].

Chemical compound and disease context of Ptger2

• We previously cloned a cDNA for a mouse PGE receptor positively coupled to adenylate cyclase from mouse mastocytoma cells, and reported it as EP2 subtype of PGE receptor [Honda, A., Sugimoto, Y., Namba, T., Watabe, A., Irie, A., Negishi, M., Narumiya, S. and Ichikawa, A. (1993) J. Biol. Chem. 268, 7759-7762] [6].
• Prostaglandin estradiol (PGE(2)) stimulates bone resorption by a cyclic AMP (cAMP)-dependent mechanism that involves prostaglandin E receptors of the EP2 and EP4 subtypes [7].
• Misoprostol, which is selective for both EP2- and EP3-receptors, inhibited the edema response to ZAS (> 40%) but had no effect on the response to PAF [8].
• Spinal prostaglandin E receptors of the EP2 subtype and the glycine receptor alpha3 subunit, which mediate central inflammatory hyperalgesia, do not contribute to pain after peripheral nerve injury or formalin injection [9].

Biological context of Ptger2

• Thus, GDF-9 induces an EP2 signal transduction pathway which appears to be required for progesterone synthesis in cumulus granulosa cells [10].
• To determine if EP2-activated protection was specific to neurons, mouse neuronal cultures were treated with butaprost, and cell viability was analyzed after 24 h of NMDA excitotoxicity [11].
• Agonists that bound EP2 or EP2 and EP4 receptors also strongly stimulated class switching to IgE [12].
• EP2 knockout mice had significantly reduced cellular proliferation of mouse skin keratinocytes in vivo and in vitro compared with that in WT mice [13].
• PGE2 and an EP2 agonist have the ability to stimulate G-CSF gene expression even in the absence of LPS [14].

Anatomical context of Ptger2

• Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells [15].
• Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway [10].
• Inhibition of the EP2 pathway in the mammary gland may be a novel approach in the prevention and/or treatment of mammary cancer [2].
• In mammary tumor cell lines, expression of the EP2 receptor followed by treatment with CAY10399, an EP2-specific agonist, strongly induced amphiregulin mRNA levels in a protein kinase A-dependent manner [2].
• Biphasic effect of prostaglandin E2 on osteoclast formation in spleen cell cultures: role of the EP2 receptor [16].

Associations of Ptger2 with chemical compounds

• In addition, GDF-9 stimulates EP2 mRNA synthesis by a prostaglandin- and progesterone-independent pathway [10].
• To further define the PGE(2)-dependent pathway, we show that butaprost, a specific EP2 agonist, stimulates progesterone synthesis and overrides the NS-398 block [10].
• Furthermore, PGE(2), an EP2 agonist (butaprost), an EP2/PGE(3) (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not [17].
• The EP2 receptor agonist butaprost did not change membrane voltage of podocytes [18].
• The goal of the current study was to determine whether EP2 receptor activation protects neurons from acute NMDA-mediated excitotoxicity [11].
• Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation [19].

Regulatory relationships of Ptger2

• Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF-alpha production [20].
• Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions [15].
• These data suggest that PGE2 signaling via the EP2 receptor in mammary epithelial cells regulate mammary gland hyperplasia by the cAMP-dependent induction of amphiregulin [2].
• PGE2 decreased the expression of messenger RNA for granulocyte-macrophage colony stimulating factor in spleen cell cultures from EP2 +/+ mice but had little effect on cells from EP2 -/- mice [21].
• However, despite this enhancement of Abeta phagocytosis, lack of EP2 completely suppressed Abeta-activated microglia-mediated paracrine neurotoxicity [22].

Other interactions of Ptger2

• PGE(2) can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF-alpha and IL-6 [20].
• 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 [23].
• Tbxa2r mapped to Chr 10, Ptgerep2 mapped to the distal end of Chr 3 [24].
• M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM [25].
• Interestingly, PGE2 utilized the same EP2 receptor-mediated signal transduction mechanism to down-regulate the expression of the inducible NO synthase and the production of NO [26].

Analytical, diagnostic and therapeutic context of Ptger2

• The mouse prostaglandin E receptor EP2 subtype: cloning, expression, and northern blot analysis [27].
• Disruption of the EP2 gene in bone marrow cells had no effect on OC formation in the cocultures, while disruption of the EP4 gene in bone marrow cells abrogated OC formation in the cocultures [28].
• Analysis using reverse transcription polymerase chain reaction revealed that the mouse ovaries express a significant amount of EP4 mRNA in addition to EP2 mRNA during superovulation [29].
• We show that the MRL-+/+ ES cell lines undergo gene targeting by homologous recombination at high frequency by inactivating the gene encoding the EP2 prostaglandin receptor [30].
• The growth-promoting effect of the EP2 agonist on chondrocytes surrounded by cartilage matrix was examined in an organ culture of rat femora [31].

References