Disease relevance of Ptger1

• Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice [1].
• Thus, EP1 antagonists may be good candidates as chemopreventive agents for colon cancer [2].
• Our results demonstrate that host EP1 and EP3 receptors are involved in the control of local tumor growth, which translates into anorexia, this being the main cause of metabolic adaptive alterations to explain weight loss in this model [3].
• Anorexia and cachexia in prostaglandin EP1 and EP3 subtype receptor knockout mice bearing a tumor with high intrinsic PGE2 production and prostaglandin related cachexia [3].
• Pharmacological inhibition or gene inactivation of EP1 receptors ameliorates brain injury induced by excitotoxicity, oxygen glucose deprivation and middle cerebral artery (MCA) occlusion [4].

Psychiatry related information on Ptger1

• Prostaglandin E receptor EP1 controls impulsive behavior under stress [5].
• We now show that, under social or environmental stress, mice deficient in prostaglandin E receptor subtype EP1 (Ptger1(-/-)) manifest behavioral disinhibition, including impulsive aggression with defective social interaction, impaired cliff avoidance, and an exaggerated acoustic startle response [5].
• 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) [6].

High impact information on Ptger1

• We therefore sought to identify the downstream effectors of COX-2 neurotoxicity, and found that prostaglandin E(2) EP1 receptors are essential for the neurotoxicity mediated by COX-2-derived prostaglandin E(2) [4].
• EP1 receptors disrupt Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange, a key mechanism by which neurons cope with excess Ca(2+) accumulation after an excitotoxic insult [4].
• Thus, EP1 receptors contribute to neurotoxicity by augmenting the Ca(2+) dysregulation underlying excitotoxic neuronal death [4].
• The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR [7].
• There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways [7].

Chemical compound and disease context of Ptger1

• Saline-injected EP1(-/-) mice showed hyperalgesia, which was reversed by i.t. PGE2 in a dose-dependent manner [8].
• 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%) [9].

Biological context of Ptger1

• Dopamine turnover in the frontal cortex and striatum was increased in Ptger1(-/-) mice, and administration of dopaminergic antagonists corrected their behavioral phenotype [5].
• A functional cDNA clone encoding a mouse EP1 subtype of prostaglandin (PG) E receptor was isolated from a mouse cDNA library by cross-hybridization with the mouse thromboxane A2 receptor cDNA [10].
• The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure [11].
• This study reveals a novel cross-talk between the EP1 receptor and EGFR signaling that synergistically promotes cancer cell growth and invasion [12].
• The exposure of these cells to EP1 agonist changed the cell shape to a more fibroblastic appearance [13].

Anatomical context of Ptger1

• These data indicate that in podocytes, PGE2 regulates distinct cellular functions via the EP1 and EP4 receptor, thereby increasing [Ca2+]i and cAMP, respectively [14].
• Strong signals for EP1 transcripts were detected in cells of the muscularis mucosae layer, especially in the body of the stomach [15].
• In addition, the HCO3- stimulatory action of sulprostone (EP1/EP3 agonist) in the stomach was inhibited by the Ca2+ antagonist verapamil but not affected by IBMX, the inhibitor of phosphodiesterase, while that in the duodenum was inhibited by verapamil and enhanced by IBMX [16].
• Immunohistochemical analysis of EP receptor staining in unirradiated and UVB-exposed SKH-1 mouse skin demonstrated the localization of EP1 and EP2 to the plasma membrane of differentiated epidermal keratinocytes [17].
• Analysis of c-Fos expression as a marker for neuronal activity indicated that both EP1 and EP3 contribute to activation of neurons in the paraventricular nucleus of the hypothalamus (PVN) [18].

Associations of Ptger1 with chemical compounds

• These results strongly suggest that prostaglandin E2 contributes to colon carcinogenesis to some extent through its action at the EP1 receptor [2].
• Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis [2].
• Administration of 250, 500, or 1000 ppm of a novel selective EP1 antagonist, ONO-8711, in the diet to azoxymethane-treated C57BL/6J mice also resulted in a dose-dependent reduction of ACF formation [2].
• 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) [19].
• The effect of PGE(2) was reproduced by the E prostanoid (EP)1 receptor agonist 17-trinor-PGE(2), and the EP1/EP3 agonist, sulprostone, but not the EP2 receptor agonist, butaprost [20].

Physical interactions of Ptger1

• These results suggest that PGE2 contributes to colon carcinogenesis through binding to the EP1 receptor [21].

Regulatory relationships of Ptger1

• The PGE2-induced phase shift is inhibited by the EP1 antagonist SC-51322 [22].
• RT-PCR revealed that EP1, EP2, and EP3 were expressed in rat calvariae and that osteoblastic cells (MC3T3-E1) expressed EP1 and EP2 [23].

Other interactions of Ptger1

• The EP1 selective agonist iloprost and the EP2 selective agonist butaprost minimally stimulated RANKL [24].
• Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid-induced HCO3- secretion in stomach [25].
• Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity [4].
• Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice [26].
• EP1 immunostaining in the PVN revealed its localization at synapses on corticotropin-releasing hormone-containing neurons [18].

Analytical, diagnostic and therapeutic context of Ptger1

• In situ hybridization, demonstrated renal expression of EP1 mRNA was exclusively over the collecting duct [27].
• Nuclease protection assays demonstrated highest expression of EP1 mRNA in kidney, followed by stomach, adrenal, and ileum [27].
• We examined the direct effect of SC-19220, an EP1 prostaglandin (PG) E2 receptor antagonist, on osteoclastogenesis induced by RANK/RANKL signaling in mouse cell cultures [28].
• Northern blot analysis revealed that EP1 and EP4 subtypes are expressed in MC3T3-E1 [13].
• A partial cDNA, corresponding to the mouse prostaglandin E2 receptor subtype EP1, was isolated from mouse brain cDNA using a degenerate primer PCR strategy [29].

References