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Prostaglandin EP3 receptor

Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

EP3 is widely distributed in humans. Its protein and/or mRNA is expressed in kidney (i.e. glomeruli, Tamm-Horsfall protein negative late distal convoluted tubules, connecting segments, cortical and medullary collecting ducts, media and endothelial cells of arteries and arterioles); stomach (vascular smooth muscle and gastric fundus mucosal cells); thalamus (anterior, ventromedial, laterodorsal, paraventricular and central medial nuclei); intestinal mucosal epithelia at the apex of crypts; myometrium (stromal cells, endothelial cells, and, in pregnancy, placenta, chorion, and amnion); mouth gingival fibroblasts; and eye (corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, and conjunctival and iridal stroma cells, and retinal Muller cells).

Numerous synthetic compounds have been found to be highly selective in binding to but not stimulating EP3. These Receptor antagonist DG-O41, L798,106, and ONO-AE3-240, block EP3 from responding to PGE2 or other agonists of this receptor, including Sulprostone, ONO-AE-248 and TEI-3356. They are in development primarily as anti-thrombotics, i.e. drugs to treat pathological blood clotting in humans.

Studies using animals genetically engineered to lack EP3 and supplemented by studies examining the actions of EP3 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP3 receptor function found in these studies does not necessarily indicate that in does do in humans. For example, EP3 receptor activation promotes duodenal secretion in mice; this function is mediated by EP4 receptor activation in humans. EP receptor functions can vary with species and most of the functional studies cited here have not translated their animal and tissue models to humans.

In a mouse model of ovalbumin-induced asthma, a selective EP3 agonist reduced airway cellularity, mucus, and bronchoconstriction responses to methacholine. In this model, EP33-deficient mice, upon ovalbumin challenge, exhibited worsened allergic inflammation as measured by increased airway eosinophils, neutrophils, lymphocytes, and pro-allergic cytokines (i.e. interleukin 4, interleukin 5, and interleukin 13) as compared to wild type mice. EP3 receptor-deficient mice and/or wild type mice treated with an EP3 receptor agonist are similarly protected from allergic responses in models of allergic conjunctivitis and contact hypersensitivity. Thus, EP3 appears to serve an important role in reducing allergic reactivity at least in mice.

Activation of EP3 receptors contracts vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, rodent and human pulmonary artery, and murine renal and brain vasculature. Mice depleted of EP3 are partially protected from brain injury consequential to experimentally induced cerebral ischemia. Furthermore, rodent studies indicate that agonist-induced activation of EP3 in the brain by intra-cerebroventricular injection of PGE2 or selective EP3 agonist cause hypertension; a highly selective EP3 receptor antagonist blocked this PGE2-induced response. These studies, which examine a sympatho-excitatory response (i.e. responses wherein brain excitation such as stroke raises blood pressure) suggest that certain hypertension responses in humans are mediated, at least in part, by EP3.

Activation of EP3 receptors on the blood platelets of mice, monkeys, and humans enhances their aggregation, degranulation, and blood clot-promoting responsiveness to a wide array of physiological (e.g. thrombin) and pathological (e.g. atheromatous plaques. (In contrast, activation of either the EP2 or EP3 receptor inhibits platelet activation) Inhibition of EP3 with the selective EP3 receptor antagonist, DG-041, has been shown to prevent blood clotting but not to alter hemostasis or blood loss in mice and in inhibit platelet activation responses in human whole blood while not prolonging bleeding times when given to human volunteers. The drug has been proposed to be of potential clinical use for the prevention of blood clotting while causing little or no bleeding tendencies.

Studies of the direct effects of EP3 receptor activation on cancer in animal and tissue models give contradictory results suggesting that this receptor does not play an important role in Carcinogenesis. However, some studies suggest an indirect pro-carcinogenic function for the EP3 receptor: The growth and metastasis of implanted Lewis lung carcinoma cells, a mouse lung cancer cell line, is suppressed in EP33 receptor deficient mice. This effect was associated with a reduction in the levels of Vascular endothelial growth factor and matrix metalloproteinase-9 expression in the tumor's stroma; expression of the pro-lymphangiogenic growth factor,VEGF-C and its receptor, VEGFR3; and a tumor-associated angiogenesis and lymphangiogenesis.