Prostaglandin EP₄ receptor

Prostaglandin E₂ receptor 4 (EP₄) is a

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).^{[7] [8]}

Expression

In humans,

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.^[13]

Mechanism of cell activation

EP₄ is classified as a relaxant type of

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.[14]

Ductus arteriosus

EP₄ plays a critical role in postnatal closure of the

To allow further studies of EP₄ function, colonies obtained by cross-breeding the 5% of mice surviving EP₄ deletion are used.[6]

Inflammation

Activation of EP₄ suppresses the production of

Gastrointestinal tract

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.^[19] 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.^[14]

Bone

Studies in mice found that the PGE₂-EP₄ pathway induces

EP₄ receptor-depleted mice exhibit slower weight gain; reduced adiposity upon high fat diet challenge; and shortened life span. These deficiencies are associated with disrupted lipid metabolism due to impaired triglyceride clearance; this impaired triglyceride clearance may underlie the cited deficiencies.[11]^[20]

Cancer

The EP₄ receptor is over-expressed in human prostate cancer tissue and a selective EP₄-receptor antagonist inhibits the growth and

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.^[21][6]

Eye

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.^[6]

Clinical significance

Translational research

Clinical translational research studies using EP₄ stimulators (i.e. agonists) or inhibitors (i.e. antagonists) that have been conducted or are underway include:

• The selective EP₄ agonist, ^name
  _rivenprost (ONO-4819), improved the ulcerative colitis symptoms of 3 among 4 tested patients in a phase 2 clinical trial finished in 2009 (https://clinicaltrials.gov/ct2/show/record/NCT00296556?term=rivenprost&rank=10) but no follow-up studies have been recorded.^[13]
• The EP₄ selective antagonist, CJ-023,423, was tested for its effectiveness in treating gastroduodenal ulcers in patients between 2006 and 2008 d with no results reported (https://clinicaltrials.gov/ct2/show/NCT00392080?term=CJ-023%2C423&rank=1) and is currently being tested in the recruitment step for a phase 2 clinical trial to treat prostate, non-small cell lung, and breast cancers (https://clinicaltrials.gov/ct2/show/NCT02538432?term=CJ-023%2C423&rank=2).^[13]
• The EP₄ selective antagonist, BGC20-1531, is being tested for its ability to block PGE₂-induced headaches in health volunteers to determine if it is a potentially useful candidate for testing its effectiveness on clinical headaches (https://clinicaltrials.gov/ct2/show/NCT00957983?term=EP4&rank=1).
• Grapiprant, a highly selective and potent EP₄ antagonist, is approved by the Food and Drug Administration for use in canine medicine to treat pain caused by inflammation such as that occurring in osteoarthritis;^[22] it is currently also under investigation for use in humans.^[23]

Genomic Studies

The A/T SNP variant, rs4434423,[31] in the 5'-untranslated region of PTGER4 has been associated with and increase rate of primary graft dysfunction in a multicentered cohort study of graph recipients of different ethnicities.^[27]

See also

• Prostaglandin E2 receptor 1 (EP1)
• Prostaglandin E2 receptor 2 (EP2)
• Prostaglandin E2 receptor 3 (EP3)
• Eicosanoid receptor

References