Prostaglandin E
2 receptor 4 (EP
4) is a
prostaglandin receptor for
prostaglandin E2
Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnanc ...
(PGE
2) encoded by the PTGER4
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in humans.
It is one of four identified EP receptors, the others being EP
1, EP
2, and EP
3, all of which bind with and mediate cellular responses to PGE
2 and also, but generally with lesser affinity and responsiveness, certain other
prostanoids
In molecular biology, prostanoids are active lipid mediators that regulate Inflammation, inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of Inflammation, inflammatory and Anaphylaxis, an ...
(see
Prostaglandin receptors
Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane Receptor (biochemistry), receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., pro ...
). EP
4 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
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
(GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see
rhodopsin-like receptors#Subfamily A14).
Expression
In humans,
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
for EP4 has been detected by
northern blot
The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample.Ke ...
ting in the heart and small intestine and to lesser extents in lung, kidney, thymus, uterus,
dorsal root ganglion
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...
s, and brain. EP4 protein is found in humans as measured by
immunochemistry
Immunochemistry is the study of the chemistry of the immune system. This involves the study of the properties, functions, interactions and production of the chemical components of the immune system. It also include immune responses and determina ...
in pulmonary veins; kidney
glomeruli and
tunica media
The tunica media (Neo-Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the internal elastic lamina of the tunica intima on the inside and the tunica externa on the outside.
Artery
The ...
of kidney arteries;
corpus cavernosum of the penis;
carotid artery Carotid artery may refer to:
* Common carotid artery, often "carotids" or "carotid", an artery on each side of the neck which divides into the external carotid artery and internal carotid artery
* External carotid artery, an artery on each side of ...
atherosclerotic plaque
An atheroma, or atheromatous plaque, is an abnormal accumulation of material in the inner layer of an arterial wall.
The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount of fibrous conne ...
s;
Abdominal aorta
In human anatomy, the abdominal aorta is the largest artery in the abdominal cavity. As part of the aorta, it is a direct continuation of the descending aorta (of the thorax).
Structure
The abdominal aorta begins at the level of the diaphragm ...
aneurysm
An aneurysm is an outward :wikt:bulge, bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also b ...
s;
cornea
The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
l endothelium, corneal
keratocytes,
trabecular cells,
cilia
The cilium (: cilia; ; in Medieval Latin and in anatomy, ''cilium'') is a short hair-like membrane protrusion from many types of eukaryotic cell. (Cilia are absent in bacteria and archaea.) The cilium has the shape of a slender threadlike proj ...
ry epithelium,
conjunctiva
In the anatomy of the eye, the conjunctiva (: conjunctivae) is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with gobl ...
l
stromal cells, and
iridal stromal
Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine muco ...
cells of the eye; and
gingiva
The gums or gingiva (: gingivae) consist of the mucosal tissue that lies over the mandible and maxilla inside the mouth. Gum health and disease can have an effect on general health.
Structure
The gums are part of the soft tissue lining of the ...
l fibroblasts.
Ligands
Activating ligands
Standard
prostanoid
In molecular biology, prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes ...
s have the following relative efficacies in binding to and activating EP
4: PGE
2>
PGF2α=
PGI2>
PGD2=
TXA2
Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by a ...
.
Prostaglandin E1
Prostaglandin E1 (PGE1) is a naturally occurring prostaglandin with various medical uses. Alprostadil and misoprostol are synthetic forms of prostaglandin E1 used as medications. Lubiprostone, a derivative of prostaglandin E1, is also used as ...
(PGE
1), which has one less
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
than PGE
2, has the same binding affinity and potency for EP
4, both PGs having high affinity (
Ki=3 nM) (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=343).
Several synthetic compounds, e.g. 1-hydroxy-PGE
1, (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 EP
4 but unlike PGE
2 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
Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
, and certain
cardiovascular disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
s.
Inhibiting ligands
Inhibitory
receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
s for EP
4, 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
EP
4 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 PGE
2 or other of its agonists, it mobilizes
G proteins containing the
Gs alpha subunit
The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein.
Gsα is the founding m ...
(i.e. Gα
s)-
G beta-gammaes (i.e. G
βγ) complex. The complex then dissociate into its Gα
s and G
βγ components which act to regulate
cell signaling
In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...
pathways. In particular, Gα
s stimulates
adenyl cyclase to raise cellular levels of
cAMP
Camp may refer to:
Areas of confinement, imprisonment, or for execution
* Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups
* Extermination ...
; cAMP activates
PKA
In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction
:H ...
, a
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
which in turn activates signaling molecules, in particular, the transcription factor,
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
. Activated CREB stimulates the expression of genes such as
c-fos
Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Ji ...
,
somatostatin
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...
, and
corticotropin-releasing hormone
Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that b ...
that regulate
cellular proliferation,
cellular differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
, cellular survival, and
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
. EP
4 activation of G proteins also activate
PI3K/AKT/mTOR,
ERK, and
p38 MAPK pathways. Activation of ERK induces expression of
EGR1
EGR-1 (Early growth response protein 1) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene.
EGR-1 is a mammalian transcription factor. It was also named Krox-24, TIS8, and ZENK. It was or ...
, a transcription factor which controls transcription of genes involved in
cellular differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
and
mitogenesis
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen.
The cell cycle
Mitogens ac ...
. EP
4 also interacts with Prostaglandin E receptor 4-associated protein (EPRAP) to inhibit phosphorylation of the
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
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; EP
4 activation may therefore have diverse effects on cell function depending on these factors.
In many respects, EP
4 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, EP
4 undergoes
homologous desensitization. That is, EP
4 becomes insensitive to further activation and internalizes. This effect limits the duration and extent to which EP
4 can stimulate cells. Agents which activate certain isoforms of
protein kinase C
In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
can also desensitize EP
4 by a process termed
heterologous desensitization.
Functions
Studies using animals genetically engineered to lack EP
4 and supplemented by studies examining the actions of EP
4 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP
4 receptor function found in these studies does not necessarily indicate that in does so in humans since EP receptor functions can vary between species.
Ductus arteriosus
EP
4 plays a critical role in postnatal closure of the
ductus arteriosus
The ductus arteriosus, also called the ductus Botalli, named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. It allows mos ...
as defined in mice lacking a functional gene for this receptor, i.e. EP
4(-/-) mice (see
Knockout mouse
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
). About 95% of EP
4(-/-) mice die within 3 days of birth due to the pulmonary congestion and heart failure caused by a patent ductus arteriosus. The ductus operates in the fetus to shunt blood from the pulmonary artery to the proximal descending aorta thereby allowing blood from the heart's right ventricle to bypass the fetus's non-functioning lungs. The ductus must close at birth to allow blood flow into the lungs. In mice, this is accomplished by turning off the mechanism which maintains the ductus's patency. Continuous activation of EP
4 by PGE
2 keeps the ductus open in the
fetus
A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
; at birth, however, levels of EP
4 and PGE
2 in the smooth muscle cells and media in mouse ductus fall. This closes the ductus thereby establishing normal post-fetal circulation of blood through the lungs. Based on studies using EP
receptor agonists
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...
and
receptor antagonists, EP
2 in mice and, at least in lambs, EP
3 may play minor parts in maintaining patency of the ductus.
These studies also appear relevant to humans:
nonsteroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...
s, particularly
indomethacin
Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of pr ...
, are used to reduce prostaglandin production and thereby close the ductus in neonates, infants, and older patients with
Patent ductus arteriosus
Patent ductus arteriosus (PDA) is a medical condition in which the ''ductus arteriosus'' fails to close after childbirth, birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs from the aorta, which has a h ...
; furthermore, prostaglandins or their analogs are used to keep the ductus open in neonates with congenital heart defects such as
Transposition of the great arteries
Transposition of the great vessels (TGV) is a group of congenital heart defects involving an abnormal spatial arrangement of any of the great vessels: superior and/or inferior venae cavae, pulmonary artery, pulmonary veins, and aorta. Congenit ...
until corrective surgery can be performed (see
Ductus arteriosus#Disorder: Patent ductus arteriosus).
To allow further studies of EP
4 function, colonies obtained by cross-breeding the 5% of mice surviving EP
4 deletion are used.
Inflammation
Activation of EP
4 suppresses the production of
IL-12p70 and increases
IL-23 thereby promoting development of
IL-17-producing
Th17 cell
T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to Regulatory T cell, T regulatory cells and the signals that cause Th17s to actually inhibit Treg diff ...
s, a subset of pro-inflammatory
T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
s that serves to maintain mucosal barriers, clear mucosal surfaces of pathogens, and contribute to autoimmune and inflammatory disorders. Its activation also: a) supports the development of
Regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg  ...
s (i.e. suppressor T cells that modulate the immune system to maintain tolerance to self-antigens and prevent autoimmune disease); b) stimulate
Dendritic cell
A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s (i.e.
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
s located primarily in the skin and mucous membranes) to mature, migrate, and direct the early stage of immune responses; c) inhibit antibody-producing
B cell
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s from proliferating; d) suppresses the development of
Atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
plaques by promoting the death (i.e.
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
) of plaque-bound pro-inflammatory
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s; e) increases the survival of neurons in an inflammation-based model of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
; f) increases local
arteriole
An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillary, capillaries.
Arterioles have vascular smooth muscle, muscular walls (usually only one to two layers of smoo ...
and
capillary
A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima (the inn ...
blood flow to cause, for example, site-specific signs of inflammation such as redness, heat, and swelling in rodent models; and g) suppresses sensory
Dorsal root ganglion
A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...
neurons from signaling inflammation-induced pain (i.e.
allodynia
Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, sunburn can cause temporary allodynia, so that usually painless stimuli, such as wearing clothing or running cold or warm water over ...
and
hyperalgesia
Hyperalgesia ( or ; ''hyper'' from Greek ὑπέρ (''huper'') 'over' + ''-algesia'' from Greek ἄλγος (algos) 'pain') is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and ...
) and has been used successfully to block the osteoarthritis pain in dogs.
Gastrointestinal tract
EP
4 receptors are highly expressed in the small intestine and colon. Mice lacking this receptor or treated with a selective EP
4 antagonist proved to be far more susceptible to the development of dextran sodium sulphate (DSS)-induced
colitis
Colitis is swelling or inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and ...
and to be protected from developing the colitis by pre-treatment with EP
4-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. EP
4 thus appears to serve anti-inflammatory and protective functions in the colon and agonists of this receptor may be useful for treating
inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
s such as
ulcerative colitis
Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
.
Activation of EP
4 stimulates
duodenum
The duodenum is the first section of the small intestine in most vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption.
The duodenum precedes the jejunum and ileum and is the shortest p ...
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.
Bone
Studies in mice found that the PGE
2-EP
4 pathway induces
osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
(i.e. cells responsible for bone absorption) to differentiate from precursor cells and is required for
IL-1beta-,
Tumor necrosis factor alpha
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
-, and
basic fibroblast growth factor-induced osteoclast formation; bone taken from EP
4(-/-) mice to re-absorb bone when induced to do so and the infusion of PGE
2 into mice failed to stimulate bone absorption. Furthermore, the infusion of selective EP
4 agonists into mice stimulated increases in the number of bone osteoclasts and
osteoblasts
Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functi ...
as well as increases in bone density. These studies indicate that the EP
4 receptor mediates bone remolding in mice and, it is suggested, other animals including humans.
Heart
In mice, EP
4 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. EP
4 receptor-depleted mice exhibit more severe cardiac damage in experimental models of
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
and
ischemic reperfusion injury but also develop cardiac hypertrophy with poor cardiac function.
Cardiac specific EP
4 deficiency using
Site-specific recombination Site-specific recombination, also known as conservative site-specific recombination, is a type of genetic recombination in which DNA strand exchange takes place between segments possessing at least a certain degree of sequence homology. Enzymes know ...
by the
Cre recombinase method to inactivate EP
4 only in cardiac muscle causes a somewhat different form of cardiac disease,
dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. C ...
, that develops within 23–33 weeks after birth in mice.
These studies are interpreted as indicating that EP
4 plays both protective and damaging roles in the heart with the protective effects of EP
4 due at least in part to its ability to suppress inflammation.
Lipid metabolism
EP
4 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.
Cancer
The EP
4 receptor is over-expressed in human prostate cancer tissue and a selective EP
4-receptor antagonist inhibits the growth and
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
of human prostate cancer cell
xenografts. An EP
4 receptor antagonist as well EP
4 Gene knockdown Gene knockdown is an experimental technique by which the expression of one or more of an organism's genes is reduced. The reduction can occur either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleot ...
inhibit the in vitro proliferation and invasiveness of human breast cancer cells. And, gene knockdown of EP
4 inhibit the
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
of murine breast cancer cells in a mouse model of induced breast cancer. PGE
2 stimulates the in vitro growth of human
non-small cell lung cancer
Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...
while an antagonist of EP
4 or EP
4 gene knockdown inhibits this growth. These results indicate that the stimulation of EP
4 promotes the growth of various types of cancer cells and therefore may play a role in the progression of certain types of human cancer.
Hearing
EP4
4 receptors are expressed in the
cochlea
The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus (cochlea), modiolus. A core component of the cochlea is the organ of Cort ...
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.
Eye
A selective EP
4 antagonists significantly reduced
corneal neovascularization
Corneal neovascularization (CNV) is the in-growth of new blood vessels from the pericorneal plexus into avascular Cornea, corneal tissue as a result of oxygen deprivation. Maintaining avascularity of the corneal stroma is an important aspect of he ...
in rats caused by
oxygen-induced retinopathy or laser-induced choroidal neovascularization. This result suggests that EP
4 activation contributes to corneal neovascularization and that EP
4 antagonists may be useful for treating neovascular eye disease.
Clinical significance
Translational research
Clinical
translational research
Translational research (also called translation research, translational science, or, when the context is clear, simply translation) is research aimed at translating (converting) results in basic research into results that directly benefit humans ...
studies using EP
4 stimulators (i.e. agonists) or inhibitors (i.e. antagonists) that have been conducted or are underway include:
*The selective EP
4 agonist, (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.
*The EP
4 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).
*The EP
4 selective antagonist, BGC20-1531, is being tested for its ability to block PGE
2-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 EP
4 antagonist, is approved by the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
for use in canine medicine to treat pain caused by inflammation such as that occurring in osteoarthritis;
it is currently also under investigation for use in humans.
Genomic Studies
Single nucleotide polymorphism
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNP) A/G variant rs10440635 close to the ''PTGER4'' gene on human chromosome 5 has been associated with an increased incidence of
Ankylosing spondylitis
Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...
in a population recruited from the United Kingdom, Australia, and Canada. Ankylosing spondylitis is a chronic inflammatory disease involving excessive bone deposition in the
Vertebral column
The spinal column, also known as the vertebral column, spine or backbone, is the core part of the axial skeleton in vertebrates. The vertebral column is the defining and eponymous characteristic of the vertebrate. The spinal column is a segmente ...
and increased expression of EP4 at vertebral column sites of involvement. Thus, excessive EP4 activation may contribute to the pathological bone remodeling and deposition found in ankylosing spondylitis and the rs10440635 variant may predispose to this disease by influencing EP4's production or expression pattern.
The GG
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
at -1254G>A in ''PTGER4'' is associated with the
non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(NSAID)-exacerbated cutaneous disease (NECD). NECD is a non-allergic
hypersensitivity
Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...
reaction involving the acute development of
wheals
A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, Nail (anatomy), nails, and related muscle and glands. The major funct ...
and
angioedema
Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...
in response to NSAID consumption in individuals with a history of chronic
urticarial
Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...
. The G allele at the -1254 position leads to lower
''PTGER4'' gene promoter function, lower levels of EP
4, and presumably thereby less of the anti-inflammatory effects of EP
4.
Several ''PTGER4'' gene variations have been associated with inflammatory bowel disease: a)
Meta-analysis
Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of
Genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait. GWA studies typically focus on assoc ...
found that SNP variant rs11742570 containing a C/T single-nucleotide variation in ''PTGER4'' is associated with an increased incidence of
Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
; b) rs4495224, an A/C SNP variant, and rs7720838, both of which are projected to be binding sites in ''PTERG4'' for the transcription factor,
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
, have been associated with Crohn's disease in three independent cohorts with the association between rs7720838 and Crohn's disease being replicated in other populations; and c) certain
alleles
An allele is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.
Alleles can differ at a single position through single nucleotide polymorphisms (SNP), but they can also have insertions and deletions ...
in 5p13.1, a
Gene desert close to ''PTGER4'', correlate with the expression levels of EP
4 as well as with the development of Crohn's disease.
The A/T SNP variant, rs4434423,
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.
See also
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Prostaglandin E2 receptor 1 (EP1)
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Prostaglandin E2 receptor 2 (EP2)
*
Prostaglandin E2 receptor 3 (EP3)
*
Eicosanoid receptor
References
External links
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Further reading
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{{Prostanoidergics
G protein-coupled receptors