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.
Gene The PTGER4 gene is located on human chromosome 5p13.1 at position p13.1 (i.e. 5p13.1), contains 7 exons, and codes for a G protein-coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14).
Expression In humans, mRNA for EP4 has been detected by northern blotting 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.
Ligands
Activating ligands Standard prostanoids have the following relative efficacies in binding to and activating EP4: PGE2>PGF2α=PGI2>PGD2=TXA2. Prostaglandin E1 (PGE1), which has one less double bond than PGE2, has the same binding affinity and potency for EP4, both PGs having high affinity (Ki=3 nM) (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=343). Several synthetic compounds, e.g. 1-hydroxy-PGE1, rivenprost (ONO-4819), OOG-308, ONO-AE1-329, AGN205203, ONO-4819, CP-734,432m AE1-329, SC-19220, SC-51089, and EP4RAG bind to and stimulate EP4 but unlike PGE2 have the advantage of being selective for this receptor over other EP receptors and are relatively resistant to being metabolically degraded. They are in development as drugs for the potential treatment of various diseases including ulcerative colitis, Alzheimer's disease, osteoporosis, and certain cardiovascular diseases.
Inhibiting ligands Inhibitory receptor antagonists for EP4, including grapiprant (CJ-023,423), ONO-AE3-208, GW627368X, AH23848, and ONO-AE2-227, are in development for possible clinical use as inhibitors of the progression of prostate, breast, colon, and lung cancers.
Mechanism of cell activation EP4 is classified as a relaxant type of prostaglandin receptor based on its ability, upon activation, to relax the contraction of certain smooth muscle preparations and smooth muscle-containing tissues that have been pre-contracted by stimulation. When bound to PGE2 or other of its agonists, it mobilizes G proteins containing the Gs alpha subunit (i.e. Gαs)-G beta-gammaes (i.e. Gβγ) complex. The complex then dissociate into its Gαs and Gβγ components which act to regulate cell signaling pathways. In particular, Gαs stimulates adenyl cyclase to raise cellular levels of cAMP; cAMP activates PKA, a kinase which in turn activates signaling molecules, in particular, the transcription factor, CREB. Activated CREB stimulates the expression of genes such as c-fos, somatostatin, and corticotropin-releasing hormone that regulate cellular proliferation, cellular differentiation, cellular survival, and angiogenesis. EP4 activation of G proteins also activate PI3K/AKT/mTOR, ERK, and p38 MAPK pathways. Activation of ERK induces expression of EGR1, a transcription factor which controls transcription of genes involved in cellular differentiation and mitogenesis. EP4 also interacts with Prostaglandin E receptor 4-associated protein (EPRAP) to inhibit phosphorylation of the proteasome protein, p105, thereby suppressing a cells ability to activate nuclear factor kappa B, a transcription factor that controls genes coding for cytokines and other elements that regulate inflammation, cell growth, and cell survival (see NF-κB#Structure). The activation of these pathways lead to variety of different types of functional responses depending on cell type, the pathways available in different cell types, and numerous other factors; EP4 activation may therefore have diverse effects on cell function depending on these factors. In many respects, EP4 actions resemble those of another type of another relaxant prostanoid receptor, EP2 but differs from the contractile prostanoid receptors, EP1 and EP3 receptors which mobilize G proteins containing the Gαq-Gβγ complex. 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.
Functions Studies using animals genetically engineered to lack EP4 and supplemented by studies examining the actions of EP4 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP4 receptor function found in these studies does not necessarily indicate that in does so in humans since EP receptor functions can vary between species.
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