Disease relevance of Ptger3

• Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced [1].
• EP3 antagonism had no effect on tumor metastasis [2].
• The augmentation of EP3-mediated cAMP synthesis was dose-dependent, without affecting the half-maximal concentration for EP4-mediated G(s)-activity, which was inhibited by a G(i) inhibitor, pertussis toxin [3].
• Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two prostaglandin E2 receptor subtypes, EP3 and EP4 [3].
• Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2.) In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice [4].

Psychiatry related information on Ptger3

• Both EP1 and EP3 receptor KO mice showed a normal circadian cycle of Tc and brief hyperthermia following psychological stress (cage-exchange stress and buddy-removal stress) [5].

High impact information on Ptger3

• Cell surface receptors for prostanoids have been characterized pharmacologically and the complementary DNAs for thromboxane A2 receptor and the EP3 subtype of the prostaglandin (PG)E receptor reveal that they belong to the seven-transmembrane-domain receptor family [6].
• Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity [6].
• In chromaffin cells, two different second messenger pathways are activated by PGE2 binding to an apparently single EP3 receptor class [6].
• Here we show that such a pathway may be mediated by PGE(2) acting at the prostaglandin E receptor EP3 [7].
• The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR [8].

Chemical compound and disease context of Ptger3

• Anorexia and cachexia in prostaglandin EP1 and EP3 subtype receptor knockout mice bearing a tumor with high intrinsic PGE2 production and prostaglandin related cachexia [9].
• Sulprostone, which is selective for EP1 and EP3 PGE-receptors, produced a potent inhibition of the edema responses to both ZAS (80%) and PAF (60%) [10].
• Thus, the PGE receptor expressed on BNu-2cl3 mast cells is of the EP3 subtype and is linked to phosphoinositide metabolism via a pertussis toxin-sensitive G protein, and this activation leads to histamine release [11].
• The selective EP3 agonist, ONO-AE-248, induced hyperalgesia at 500 pg kg(-1) in EP3(+/+) mice, but not in EP3(-/-) mice [12].

Biological context of Ptger3

• Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation [13].
• Here we show that at least four isoforms of the EP3 receptor, which differ only at their C-terminal tails and are produced by alternative splicing, couple to different G proteins to activate different second messenger systems [6].
• A functional cDNA clone encoding mouse EP2 subtype of prostaglandin (PG) E receptor was isolated from a mouse cDNA library by cross-hybridization with the mouse EP3 subtype PGE receptor cDNA [14].
• The point mutation of His(140) into Phe was effective in another EP3 variant in which its C-terminal tail is different or lacking [15].
• Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development [16].

Anatomical context of Ptger3

• 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) [17].
• The results suggest the important roles of COX-2 induction and the PGE2-EP3 receptor system in the dorsal root ganglia in the development but not maintenance of acute herpetic pain [18].
• Expression of EP3 and FP primarily in the circular muscle of the myometrium on Days 3-5 of pregnancy suggests that the circular muscle, not the longitudinal muscle, is the primary target for PG-mediated uterine contractions required for embryo transport, spacing, and/or accommodation in the uterus [17].
• In conclusion, these findings suggest that PGE(2) accelerates RGD-dependent adhesion via cooperative activation between EP3 and EP4 and contributes to the recruitment of mast cells to the ECM during inflammation [3].
• Expression of EP1 in the liver and EP4 receptor in white adipose tissue were upregulated and responded to indomethacin treatment, while downregulated expression of EP3 in skeletal muscle from tumor-bearing mice was unresponsive to indomethacin treatment despite improved carcass weight [19].

Associations of Ptger3 with chemical compounds

• We examined the development of aberrant crypt foci (ACFs), putative preneoplastic lesions of the colon, in two lines of knockout mice, each deficient in prostaglandin E receptors, EP1 and EP3, by treatment with the colon carcinogen, azoxymethane [20].
• 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 [21].
• Involvement of cyclooxygenase-2 and EP3 prostaglandin receptor in acute herpetic but not postherpetic pain in mice [18].
• PGE(2) increased gastric HCO(3)(-) secretion in both rats and WT mice, and this action was inhibited by ONO-8711 and disappeared in EP1 (-/-) but not EP3 (-/-) mice [22].
• Furthermore, treatment with piroxicam results in significantly lower [Ca(2+)](i) in tumors, and this effect is attenuated by concomitant treatment with the EP1/EP3 receptor agonist 17-phenyl-trinor-PGE(2) [23].

Physical interactions of Ptger3

• Among them, EP2 and EP4 couple to Gs and EP3 to Gi [24].

Regulatory relationships of Ptger3

• RT-PCR revealed that EP1, EP2, and EP3 were expressed in rat calvariae and that osteoblastic cells (MC3T3-E1) expressed EP1 and EP2 [25].
• PGE2 worked as a mediator of febrile responses to both endogenous and exogenous pyrogens and as a regulator of bicarbonate secretion induced by acid-stimulation in the duodenum via the EP3 [26].
• Rat hepatocytes have previously been reported to possess prostaglandin E2 receptors of the EP3-type (EP3-receptors) that inhibit glucagon-stimulated glycogenolysis by decreasing cAMP [27].

Other interactions of Ptger3

• Mapping of the genes encoding mouse thromboxane A2 receptor and prostaglandin E receptor subtypes EP2 and EP3 [28].
• Unlike EP3 knockout mice, the EP2 knockout mice produced significantly fewer tumors and reduced tumor incidence compared with wild type (WT) mice in a 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage carcinogenesis protocol [29].
• The mRNA for EP3 subtype, which is coupled to inhibition of adenylate cyclase, was located densely in the tubules in the outer medulla and in the distal tubules in the cortex [30].
• Butaprost (EP2 agonist) but not sulprostone (EP3 agonist) inhibited IL-6-stimulated proliferation [31].
• CGRP level during ethanol perfusion was not increased in IP(-/-) but was increased in EP3(-/-) and wild-type counterparts after preperfusion of 1 mol/L NaCl [32].

Analytical, diagnostic and therapeutic context of Ptger3

• To study the functions of one of these subtypes, the EP3 receptor, we generated EP3-deficient (-/-) mice by gene targeting [33].
• In contrast, EP3 subtype was not detected by either Northern blot analysis or RT-PCR [34].
• Furthermore, in EP3 receptor KO mice subcutaneous injection of turpentine did not induce fever [5].
• Expression and site-directed mutagenesis of mouse prostaglandin E2 receptor EP3 subtype in insect cells [35].
• A cDNA encoding for mouse prostaglandin E2 (PGE2) receptor EP3 subtype was cloned from a mouse kidney cDNA library by PCR using terminal primers derived from the known sequence of mouse lung EP3 receptor cDNA [35].

References