# Prostaglandin EP2 receptor

Prostaglandin E$_2$ receptor 2, also known as EP$_2$, is a prostaglandin receptor for prostaglandin E2 (PGE$_2$) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP$_1$, EP$_3$, and EP$_4$, which bind with and mediate cellular responses to PGE$_2$ and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

## Gene

The PTGER2 gene is located on human chromosome 14 at position p22.1 (i.e. 14q22.1), contains 2 introns and 3 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

EP$_2$ 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.
EP$_2$ 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 EP$_2$ expression is regulated by this methylation.

## Ligands
### Activating ligands

The following standard prostaglandins have the following relative efficacies in binding to and activating EP$_2$: PGE$_2$>PGF2alpha>=PGI2>PGD2. The receptor binding affinity Dissociation constant K$_d$ (i.e. ligand concentration needed to bind with 50% of available EP$_1$ receptors) is ~13 nM for PGE2 and ~10 nM for PGE1 with the human receptor and ~12 nM for PGE$_2$ with the mouse receptor. Because PGE$_2$ activates multiple prostanoid receptors and has a short half-life in vivo due to its rapidly metabolism in cells by omega oxidation and beta oxidation, metabolically resistant EP$_2$-selective activators are useful for the study of this receptor's function and could be clinically useful for the treatment of certain diseases. There are several such agonists including butaprost free acid and ONO-AE1-259-01 which have K$_i$ inhibitory binding values (see Biochemistry#Receptor/ligand binding affinity) of 32 and 1.8 NM, respectively, and therefore are respectively ~2.5-fold less and 7-fold more potent than PGE$_2$.

### Inhibiting ligands

PF-04418948 (K$_i$=16 nM), TG4-155 (K$_i$=9.9 nM), TG8-4, and TG6-129 are selective competitive antagonists for EP$_2$ that have been used for studies in animal models of human diseases. Many of the earlier EP$_2$ receptor antagonists used for such studies exhibited poor receptor selectivity, inhibiting, for example, other EP receptors.

## Mechanism of cell activation

EP$_2$ is classified as a relaxant type of prostanoid receptor based on its ability, upon activation, to relax certain types of smooth muscle (see Prostaglandin receptors). When initially bound to PGE$_2$ or any other of its agonists, it mobilizes G proteins containing the Gs alpha subunit (i.e. Gα$_s$)-G beta-gamma complexes (i.e. G$_{βγ}$). The Gα$_s$- G$_{βγ}$ complexes dissociate into their Gα$_s$ and G$_{βγ}$ subunits which in turn regulate cell signaling pathways. In particular, Gα$_s$ stimulates adenylyl cyclase to raise cellular levels of cAMP thereby activating PKA; PKA activates various types of signaling molecules such as the transcription factor CREB which lead to different types of functional responses depending on cell type. EP$_2$ also activates the a) GSK-3 pathway which regulates cell migratory responses and innate immune responses including pro-inflammatory cytokine and interleukin production and b) Beta-catenin pathway which regulates not only cell–cell adhesion but also activates the Wnt signaling pathway which, in turn, stimulates the transcription of genes responsible for regulating cell migration and proliferation. In many of these respects, EP$_2$ actions resemble those of another type of relaxant prostanoid receptor, EP$_4$ but differs from the contractile prostanoid receptors, EP$_1$ and EP$_3$ receptors which mobilize G proteins containing the Gα$_q$-Gβγ complex. EP$_2$ also differs from all the other prostaglandin receptors in that it fails to undergo homologous desensitization. That is, following agonist-induced activation, the other prostaglandin (as well as most types of G protein coupled receptors) quickly become desensitized, often internalized, and whether or not internalized, incapable of activating their G protein targets. This effect limits the duration and extent to which agonists can stimulate cells. EP$_2$, by failing to become desensitized, is able to function over prolong periods and later time points than other prostaglandin receptors and therefore potentially able to contribute to more delayed and chronic phases of cellular and tissue responses.

## Functions

Studies using animals genetically engineered to lack EP$_2$ and supplemented by studies examining the actions of EP$_2$ receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions.

### Eye

When applied topically into the eyes of rodents, cats, rhesus monkeys, and humans PGE2 acts, apparently acting at least in part through EP$_2$, decreases intraocular pressure by stimulating increases in the drainage of aqueous humor through the uveoskceral pathway, the principal aqueous humor outflow pathway in the eye.

### Reproduction

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 EP$_2$ 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.

### Inflammation and allergy

Activation of EP$_2$ contributes to regulating B cell immunoglobulin class switching, maturation of T lymphocyte CD4−CD8− cells to CD4+CD8+ cells, and the function of Antigen-presenting cells, particularly Dendritic cells. EP thereby contributes to the development of inflammation in rodent models of certain types of experimentally-induced joint and paw inflammation and the neurotoxic effects of endotoxin. However, EP$_2$ activation also has anti-inflammatory actions on pro-inflammatory cells (e.g. neutrophils, monocytes, macrophages, dendritic cells, NK cells, TH1 cells, TH2 cells, and fibroblasts in various tissues and on microglia cells in the central nervous system). These actions suppress certain forms of inflammation such NMDA receptor-related neurotoxicity and the rodent model of Bleomycin-induced pulmonary fibrosis. EP$_2$ activation also inhibits the phagocytosis and killing of pathogens by alveolar macrophages; these effects may serve an anti-inflammatory role but reduce host defense against these pathogens.
Activation of EP$_2$ 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.

### Cardiovascular

EP$_2$ receptor-deficient mice develop mild systolic and/or systemic hypertension which is worsened by high dietary intake of salt. These effects are thought to be due to the loss of EP$_2$'s vasodilation effects and/or ability to increase the urinary excretion of salt.

### Bone

EP$_2$-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, EP$_2$-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.

### Nervous system

EP$_2$ deficient mice exhibit reduced Oxidative stress and beta amyloid formation. Activation of this receptor also has neuroprotective effects in models of Alzheimer's disease, Amyotrophic lateral sclerosis, multiple sclerosis, and stroke while its inhibition reduces Epileptic seizure. EP2 signaling can also increase stroke injury via neurons in a mice model according to a PNAS paper. EP$_2$ receptors on either nerve or Neuroglia cells of the peripheral and central nervous system act to promote pain perception, which are caused by inflammation, muscle stretch, temperature, and physical stimuli (see allodynia) in mice. A 2021 study found that inhibition of myeloid cell EP2 signalling can reverse or prevent an inflammation element of brain-ageing in mice.

### Malignancy

The EP$_2$ receptor can act as a tumor promoter. EP$_2$ 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 EP$_2$-mediated: Vascular endothelial growth factor production and thereby of tumor vascularization; regulation of endothelial cell motility and survival; interference with transforming growth factor-β's anti-cell proliferation activity; and, more recently, regulation of host anti-tumor immune responses.

## Clinical significance
### Therapeutics

Preclinical studies, as outlined above, indicate that EP$_2$ may be a target for treating and/or preventing particular human disorders involving: allergic diseases such as asthma and rhinitis, particularly aspirin-exacerbated respiratory disease (AERD); glaucoma; various diseases of the nervous system; fractures, osteoporosis, and other bone abnormalities; pulmonary fibrosis; certain forms of malignant disease such as colon cancer including those that arise from Adenomatous polyposis coli mutations; and salt-sensitive forms of hypertension; This receptor has also been suggested to be a target for contraception. To date, however, there has been little translational research to determine the possible beneficial effects of EP$_2$ antagonists or agonists in humans. The following drugs that act on EP$_2$ but also other prostaglandin receptors are in clinical use:
* Iloprost activates EP$_2$, EP$_3$, and EP$_4$ receptors to treat diseases involving pathological constriction of blood vessels such as pulmonary hypertension, Raynauds disease, and scleroderma. Presumably, it works by stimulating EP$_2$, and EP$_4$ receptors which have vasodilation actions.
* Misoprostol, an EP$_3$ and EP$_4$ receptor agonist, to prevent ulcers; to induce labor in pregnancy, medical abortion, and late miscarriage; and to prevent and treat postpartum bleeding.
The following drugs are in development or proposed to be candidates for development as highly selective EP$_2$ agonists for the indicated conditions:
* Butaprost for the treatment of pulmonary fibrosis and certain neurological diseases
* CP533,536 for the stimulation of bone formation
* Taprenepag isopropyl (PF-04217329) for the treatment of glaucoma and various neurological diseases (see above section on Nervous system)

### Genomic studies

The single-nucleotide polymorphism (SNP) variant rs17197 in the 3' untranslated region of PTGER2 has been associated with an increased incidence of essential hypertension in a population of Japanese men. SNP variant rs1254598 in a Spanish population; SNP variant uS5 located in a STAT-binding consensus sequence of the regulatory region of PTGER2 with reduced transcription activity in a Japanese population; and two PTGER2 SNP variants (-616C>G and -166G>A) in a Korean population have been associated with an increased incidence of Aspirin-induced asthma.