Prostaglandin EP4 receptor
Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, 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). EP4 has been implicated in various physiological and pathological responses in animal models and humans.
In humans, mRNA for EP4 has been detected by Northern bloting in the heart and small intestine and to lesser extents in lung, kidney, thymus, uterus, dorsal root ganglions, and brain. EP4 protein is found in humans as measured by immunochemistry in pulmonary veins; kidney glomeruli and Tunica media of kidney arteries; corpus cavernosum of the penis; carotid artery atherosclerotic plaques; Abdominal aorta aneurysms; corneal endothelium, corneal keratocytes, trabecular cells, ciliary epithelium, conjunctival stromal cells, and iridal stromal cells of the eye; and gingival fibroblasts.
Following its activation, EP4 undergoes homologous desensitization. That is, EP4 becomes insensitive to further activation and internalizes. This effect limits the duration and extent to which EP4 can stimulate cells. Agents which activate certain isoforms of protein kinase C can also desensitize EP4 by a process termed heterologous desensitization.
EP4 receptors are highly expressed in the small intestine and colon. Mice lacking this receptor or treated with a selective EP4 antagonist proved to be far more susceptible to the development of dextran sodium sulphate (DSS)-induced colitis and to be protected from developing the colitis by pre-treatment with EP4-selective agonists (ONO-AE1-734 and AGN205203). The DDS-inflicted lesions were associated with defective colon mucosa barrier function along with the overexpression of genes mediating inflammatory responses and under-expression of genes involved in mucosal repair and remodeling. EP4 thus appears to serve anti-inflammatory and protective functions in the colon and agonists of this receptor may be useful for treating inflammatory bowel diseases such as ulcerative colitis. Activation of EP4 stimulates duodenum epithelial cells to secrete bicarbonate (HCO3-) in mice and humans; this response neutralizes the acidic fluid flowing from the stomach thereby contributing to the process of intestinal ulcer healing. Activators of this receptor therefore may useful as anti-ulcer drugs.
In mice, EP4 receptor agonists reduce the acute rejection of transplanted hearts, prolong the survival of heart-transplanted animals, and reduce cardiac damage in a model of ischemic reperfusion injury but also stimulate cardiac hypertrophy accompanied by poor cardiac function. EP4 receptor-depleted mice exhibit more severe cardiac damage in experimental models of myocardial infarction and ischemic reperfusion injury but also develop cardiac hypertrophy with poor cardiac function. Cardiac specific EP4 deficiency using Site-specific recombination by the Cre recombinase method to inactivate EP4 only in cardiac muscle causes a somewhat different form of cardiac disease, dilated cardiomyopathy, that develops within 23–33 weeks after birth in mice. These studies are interpreted as indicating that EP4 plays both protective and damaging roles in the heart with the protective effects of EP4 due at least in part to its ability to suppress inflammation.
The EP4 receptor is over-expressed in human prostate cancer tissue and a selective EP4-receptor antagonist inhibits the growth and metastasis of human prostate cancer cell xenografts. An EP4 receptor antagonist as well EP4 Gene knockdown inhibit the in vitro proliferation and invasiveness of human breast cancer cells. And, gene knockdown of EP4 inhibit the metastasis of murine breast cancer cells in a mouse model of induced breast cancer. PGE2 stimulates the in vitro growth of human non-small cell lung cancer while an antagonist of EP4 or EP4 gene knockdown inhibits this growth. These results indicate that the stimulation of EP4 promotes the growth of various types of cancer cells and therefore may play a role in the progression of certain types of human cancer.
EP44 receptors are expressed in the cochlea of the inner ear. Pre- and post-treatment of guinea pigs with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses and significantly reduced the loss of outer hair cells caused by prior noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment may be a means for attenuating noise-induced hearing lose.
A selective EP4 antagonists significantly reduced corneal neovascularization in rats caused by oxygen-induced retinopathy or laser-induced choroidal neovascularization. This result suggests that EP4 activation contributes to corneal neovascularization and that EP4 antagonists may be useful for treating neovascular eye disease.