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Prostaglandin EP2 receptor

Prostaglandin E2 receptor 2 (53kDa), also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

EP2 is widely distributed in humans. Its protein is expressed in human small intestine, lung, media of arteries and arterioles of the kidney, thymus, uterus, brain cerebral cortex, brain striatum, brain hippocampus, corneal epithelium, corneal choriocapillaries, Myometriuml cells, eosinophiles, sclera of the eye, articular cartilage, the corpus cavernosum of the penis, and airway smooth muscle cells; its mRNA is expressed in gingival fibroblasts, monocyte-derived dendritic cells, aorta, corpus cavernosum of the penis, articular cartilage, airway smooth muscle, and airway epithelial cells. In rats, the receptor protein and/or mRNA has been found in lung, spleen, intestine, skin, kidney, liver, long bones, and rather extensively throughout the brain and other parts of the central nervous system.

EP2 expression in fibroblasts from the lungs of mice with Bleomycin-induced pulmonary fibrosis and humans with Idiopathic pulmonary fibrosis is greatly reduced. In both instances, this reduced expression was associated with hypermethylation of CpG dinucleotide sites located in the first 420 base pairs upstream of the PTGER2 gene transcription start site of these fibroblasts. This suggests that EP2 expression is regulated by this methylation.

Studies using animals genetically engineered to lack EP2 and supplemented by studies examining the actions of EP2 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions.

Female mice engineered to lack a functional Pgter2 gene show a modest reduction in ovulation and more severely impaired capacity for Fertilisation. Studies suggest that this impaired fertilization reflects the loss of EP2 functions in stimulating cumulus cells clusters which surround oocytes to: a) form the CCL7 chemokine which serves as a chemoattractant that guides sperm cells to oocytes and b) disassemble the extracellular matrix which in turn allows sperm cells to penetrate to the oocyte. These data allow that an EP2 receptor antagonist may be a suitable candidate as a contraceptive for women.

Activation of EP2 also influences allergic inflammatory reactions. It dilates airways (bronchodilation) contracted by the allergic mediator, histamine; inhibits Immunoglobulin E-activated mast cells from releasing histamine and leukotrienes (viz., LTC4, LTD4, and LTE4), all of which have bronchoconstricting and otherwise pro-allergic actions; inhibits pro-allergic eosinophil apoptosis, chemotaxis, and release of pro-allergic granule contents; and reduces release of the pro-allergic cytokines Interleukin 5, Interleukin 4, and interleukin 13 from human blood mononuclear cells.

EP2-deficient mice exhibit impaired generation of osteoclasts (cells that break down bone tissue) due to a loss in the capacity of osteoblastic cells to stimulate osteoclast formation. These mice have weakened bones compared with the wild type animals. When administered locally or systemically to animals, EP2-selective agonists stimulate the local or systemic formation of bone, augment bone mass, and accelerate the healing of fractures and other bone defects in animal models.

The EP2 receptor can act as a tumor promoter. EP2 gene knockout mice have less lung, breast, skin, and colon cancers following exposure to carcinogens. Knockout of this gene in mice with the adenomatous polyposis coli mutation also causes a decrease in the size and number of pre-cancerous intestinal polyps that the animals develop. These effects are commonly ascribed to the loss of EP2-mediated: Vascular endothelial growth factor production and thereby of tumor vascularization; regulation of endothelial cell motility and survival; interference with transformng growth factor-'s anti-cell proliferation activity; and, more recently, regulation of host anti-tumor immune responses.