HGNC Approved Gene Symbol: PTGER2
Cytogenetic location: 14q22.1 Genomic coordinates (GRCh38): 14:52,314,312-52,328,598 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q22.1 | {Asthma, aspirin-induced, susceptibility to} | 208550 | Autosomal recessive | 3 |
For background information on prostaglandin E receptors, see PTGER1 (176802).
Prostaglandin E2 (PGE2), one of various oxygenated metabolites of arachidonic acid, produces a broad range of biologic actions in diverse tissues. Not only are PGE2 and thromboxane A2 (188070) structurally related, but their receptors are also homologous. Taketo et al. (1994) cloned mouse cDNA sequences for PGE2 receptor subtypes EP2 (PTGER2) and EP3 (PTGER3; 176806).
In their review, Sugimoto and Narumiya (2007) summarized findings on EP receptor expression gained through Northern blot analysis of mouse tissues. They stated that mouse Ep2 mRNA was expressed predominantly in uterus, with much weaker expression in thymus, heart, stomach, and ileum, and no expression in other tissues examined.
Prostanoid receptors of the EP1 (176802), EP2, EP3, and EP4 (601586) types cloned in the mouse and/or human were reviewed by Coleman et al. (1994).
Epithelial tumors may be regulated by cyclooxygenase (COX) enzyme products. To determine if COX2 (600262) expression and PGE2 synthesis are upregulated in cervical cancers, Sales et al. (2001) used real-time quantitative PCR and Western blot analysis to confirm COX2 RNA and protein expression in squamous cell carcinomas and adenocarcinomas. In contrast, minimal expression of COX2 was detected in histologically normal cervix. Immunohistochemical analyses localized COX2 expression and PGE2 synthesis to neoplastic epithelial cells of all squamous cell carcinomas and adenocarcinomas studied. Immunoreactive COX2 and PGE2 were also colocalized to endothelial cells lining the microvasculature. To establish whether PGE2 has an autocrine/paracrine effect in cervical carcinomas, the authors investigated the expression of 2 subtypes of PGE2 receptors, namely EP2 and EP4 by real-time quantitative PCR. Expression of EP2 and EP4 receptors was significantly higher in carcinoma tissue than in histologically normal cervix. The authors concluded that COX2, EP2, and EP4 expression and PGE2 synthesis are upregulated in cervical cancer tissue and that PGE2 may regulate neoplastic cell function in cervical carcinoma in an autocrine/paracrine manner via the EP2/EP4 receptors.
Castellone et al. (2005) showed that PGE2 stimulates colon cancer cell growth through its heterotrimeric G protein-coupled receptor EP2 by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt (164730) by free G-protein beta-gamma subunits and the direct association of the G-protein alpha-S subunit (139320) with the regulator of G-protein signaling (RGS) domain of axin (603816). This leads to the inactivation and release of glycogen synthase kinase 3-beta (605004) from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin (116806) and activating its signaling pathway. Castellone et al. (2005) concluded that these findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.
In their review, Sugimoto and Narumiya (2007) stated that mouse Ep2 and Ep4 receptors couple to G(s) and mediate increases in cAMP concentrations. These Ep receptors often function redundantly when coexpressed, but in dendritic cells, Ep4, but not Ep2, regulates cell migration.
By analysis of a panel of DNA samples from an interspecific cross that had been characterized for over 500 genetic markers throughout the genome, Taketo et al. (1994) mapped the PTGER2 gene to mouse chromosome 15. They suggested that the human homolog may be on 5p since the mouse gene is located only 2 cM distal to the growth hormone receptor gene (GHR; 600946). By Southern and fluorescence in situ hybridization analysis, Smock et al. (1999) mapped the PTGER2 gene to chromosome 14q22.
Using mice deficient in the prostaglandin EP2 receptor, Tilley et al. (1999) showed that Ep2 -/- females are infertile secondary to failure of the released ovum to become fertilized in vivo. Ep2 -/- ova could be fertilized in vitro, suggesting that in addition to previously defined roles, prostaglandins may contribute to the microenvironment in which fertilization takes place. Besides its effects on reproduction, PGE2 regulates regional blood flow in various vascular beds. Mice deficient in the PGE2 EP2 receptor displayed resting systolic blood pressure that was significantly lower than that in wildtype controls. Blood pressure increased in these animals when they were placed on a high salt diet, suggesting that the EP2 receptor may be involved in sodium handling by the kidney.
Reinold et al. (2005) demonstrated that Ptger2-null mice completely lacked spinal PGE2-evoked hyperalgesia, and after peripheral inflammatory stimuli they exhibited only short-lasting peripheral hyperalgesia but lacked a second sustained hyperalgesic phase of spinal origin. Electrophysiologic recordings identified diminished synaptic inhibition of excitatory dorsal horn neurons as the dominant source of Ptger2-dependent hyperalgesia. Reinold et al. (2005) concluded that PGE2 receptors of the EP2 subtype (PTGER2) are key signaling elements in spinal inflammatory hyperalgesia.
Neuronal death caused by stroke or cardiac arrest (global ischemia) is believed to involve excitotoxicity due to overactivation of glutamate receptors, particularly those that respond to NMDA (see 138249). Liu et al. (2005) demonstrated that activation of the murine Ep2 receptor by butaprost protected mouse hippocampal neurons against NMDA-mediated toxicity in vitro. The protective effect was observed both with butaprost pretreatment as well as with butaprost treatment up to 3 hours after stimulation with NMDA, demonstrating a 'rescue' effect. In a mouse model of permanent focal ischemia via electrocoagulation of the middle cerebral artery, Ep2-null mice showed greater volumes of cerebral cortical infarct compared to controls, suggesting that the Ep2 receptor protects neurons against anoxic injury.
By genotyping 198 Japanese patients with AIA (208550) and 274 Japanese controls, Jinnai et al. (2004) found significant association of the phenotype (permutation p = 0.001) with a G/A SNP (uS5) in the 5-prime promoter region of the PTGER2 gene. Analysis of haplotypes constructed according to the linkage disequilibrium pattern showed a significant association with AIA (permutation P = 0.001). The uS5 SNP is located in the regulatory region of the PTGER2 gene in a STAT-binding consensus sequence. Although STAT1 (600555) binding was not observed in gel mobility shift assay with HeLa nuclear extract, an unidentified protein was specifically bound to the allelic sequence. In vitro reporter assay of the site containing the uS5 allele showed reduced transcription activity. Jinnai et al. (2004) hypothesized that the uS5 allele may serve as a target for a transcription repressor protein or that a functional effect of the uS5 allele may decrease transcription, resulting in reduction of the PGE2 braking mechanism of inflammation and contributing to the molecular mechanism underlying AIA.
Castellone, M. D., Teramoto, H., Williams, B. O., Druey, K. M., Gutkind, J. S. Prostaglandin E2 promotes colon cancer cell growth through a GS-axin-beta-catenin signaling axis. Science 310: 1504-1510, 2005. [PubMed: 16293724] [Full Text: https://doi.org/10.1126/science.1116221]
Coleman, R. A., Smith, W. L., Narumiya, S. VIII. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharm. Rev. 46: 205-229, 1994. [PubMed: 7938166]
Jinnai, N., Sakagami, T., Sekigawa, T., Kakihara, M., Nakajima, T., Yoshida, K., Goto, S., Hasegawa, T., Koshino, T., Hasegawa, Y., Inoue, H., Suzuki, N., Sano, Y., Inoue, I. Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum. Molec. Genet. 13: 3203-3217, 2004. [PubMed: 15496426] [Full Text: https://doi.org/10.1093/hmg/ddh332]
Liu, D., Wu, L., Breyer, R., Mattson, M. P., Andreasson, K. Neuroprotection by the PGE2 EP2 receptor in permanent focal ischemia. Ann. Neurol. 57: 758-761, 2005. [PubMed: 15852374] [Full Text: https://doi.org/10.1002/ana.20461]
Reinold, H., Ahmadi, S., Depner, U. B., Layh, B., Heindl, C., Hamza, M., Pahl, A., Brune, K., Narumiya, S., Muller, U., Zeilhofer, H. U. Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J. Clin. Invest. 115: 673-679, 2005. [PubMed: 15719070] [Full Text: https://doi.org/10.1172/JCI23618]
Sales, K. J., Katz, A. A., Davis, M., Hinz, S., Soeters, R. P., Hofmeyr, M. D., Millar, R. P., Jabbour, H. N. Cyclooxygenase-2 expression and prostaglandin E2 synthesis are up-regulated in carcinomas of the cervix: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J. Clin. Endocr. Metab. 86: 2243-2249, 2001. [PubMed: 11344234] [Full Text: https://doi.org/10.1210/jcem.86.5.7442]
Smock, S. L., Pan, L. C., Castleberry, T. A., Lu, B., Mather, R. J., Owen, T. A. Cloning, structural characterization, and chromosomal localization of the gene encoding the human prostaglandin E2 receptor EP2 subtype. Gene 237: 393-402, 1999. [PubMed: 10521663] [Full Text: https://doi.org/10.1016/s0378-1119(99)00323-6]
Sugimoto, Y., Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 282: 11613-11617, 2007. [PubMed: 17329241] [Full Text: https://doi.org/10.1074/jbc.R600038200]
Taketo, M., Rochelle, J. M., Sugimoto, Y., Namba, T., Honda, A., Negishi, M., Ichikawa, A., Narumiya, S., Seldin, M. F. Mapping of the genes encoding mouse thromboxane A2 receptor and prostaglandin E receptor subtypes EP2 and EP3. Genomics 19: 585-588, 1994. [PubMed: 7910583] [Full Text: https://doi.org/10.1006/geno.1994.1113]
Tilley, S. L., Audoly, L. P., Hicks, E. H., Kim, H.-S., Flannery, P. J., Coffman, T. M., Koller, B. H. Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E-2 receptor. J. Clin. Invest. 103: 1539-1545, 1999. [PubMed: 10359563] [Full Text: https://doi.org/10.1172/JCI6579]