Prostaglandin E
2 receptor 4 (EP
4) is a
prostaglandin receptor 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., pros ...
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 pregnancy, and ...
(PGE
2) encoded by the PTGER4
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
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
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 (mediators of vasocons ...
(see
Prostaglandin receptors Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2, (i.e. PGD2 ...
). 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 p ...
(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.K ...
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 dorsa ...
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 (antibodies/immunoglobulins, toxin, epitopes of proteins like CD4, a ...
in pulmonary veins; kidney
glomeruli
''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to:
* the filter ...
and
Tunica media
The tunica media (New Latin "middle coat"), or media for short, is the middle tunica (layer) of an artery or vein. It lies between the tunica intima on the inside and the tunica externa on the outside.
Artery
Tunica media is made up of smooth m ...
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 t ...
atherosclerotic plaque
An atheroma, or atheromatous plaque, is an abnormal and reversible 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 o ...
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 thoracic d ...
aneurysm
An aneurysm is an outward 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 be a nidus (s ...
s;
cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power ...
l endothelium, corneal
keratocytes,
trabecular cells,
cilia
The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
ry epithelium,
conjunctiva
The conjunctiva 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 goblet cells, stratified columnar epithelium ...
l
stromal cells, and
iridal stromal cells of the eye; and
gingiva
The gums or gingiva (plural: ''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 lini ...
l fibroblasts.
Ligands
Activating ligands
Standard
prostanoid
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 (mediators of vasocons ...
s have the following relative efficacies in binding to and activating EP
4: PGE
2>
PGF2α=
PGI2
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosten ...
>
PGD2
Prostaglandin D2 (or PGD2) is a prostaglandin that binds to the receptor PTGDR (DP1), as well as CRTH2 (DP2). It is a major prostaglandin produced by mast cells – recruits Th2 cells, eosinophils, and basophils. In mammalian organs, large amou ...
=
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 ac ...
.
Prostaglandin E1
Prostaglandin E1 (PGE1), also known as alprostadil, is a naturally occurring prostaglandin which is used as a medication. In infants with congenital heart defects, it is delivered by slow injection into a vein to open the ductus arteriosus unti ...
(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 a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
, and certain
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
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 rece ...
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 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., pros ...
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
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
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 me ...
(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) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
pathways. In particular, Gα
s stimulates
adenyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
to raise cellular levels of
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
; cAMP activates
PKA, 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–Jinkin ...
,
somatostatin
Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...
, 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 (biology), stress responses. It is a releasing ...
that regulate
cellular proliferation,
cellular differentiation
Cellular differentiation is the process in which a stem cell alters 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 multicellular ...
, 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 by processes of sprouting and splitting ...
. EP
4 activation of G proteins also activate
PI3K/AKT/mTOR,
ERK, and
p38 MARK pathways. Activation of ERK induces expression of
EGR1
EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) 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 wa ...
, a transcription factor which controls transcription of genes involved in
cellular differentiation
Cellular differentiation is the process in which a stem cell alters 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 multicellular ...
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 mechanism of action of a ...
. EP
4 also interacts with Prostaglandin E receptor 4-associated protein (EPRAP) to inhibit phosphorylation of the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
protein,
p105, thereby suppressing a cells ability to activate
nuclear factor kappa B
Nuclear may refer to:
Physics
Relating to the Atomic nucleus, nucleus of the atom:
*Nuclear engineering
*Nuclear physics
*Nuclear power
*Nuclear reactor
*Nuclear weapon
*Nuclear medicine
*Radiation therapy
*Nuclear warfare
Mathematics
*Nuclear ...
, 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
Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration. It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cel ...
. 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 Heterologous desensitization (also known as cross-desensitization) is the term for the unresponsiveness of cells to one or more agonists to which they are normally responsive. Typically, desensitization is a receptor (biochemistry)-based phenomenon ...
.
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 allo ...
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 (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
; 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 ag ...
and
receptor antagonists
A receptor antagonist is a type of Receptor (biochemistry), receptor ligand (biochemistry), ligand or drug that blocks or dampens a biological response by binding to and blocking a Receptor (biochemistry), receptor rather than activating it like ...
, 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 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 ...
s, particularly
indomethacin
Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription drug, prescription medication to reduce fever, pain, joint stiffness, stiffness, and swelling (medical), swelling from infl ...
, 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 birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has ...
; 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. Congenita ...
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 cells, 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 tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
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
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their 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 that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s located primarily in the skin and mucus 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 white blood cell 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 ...
s from proliferating; d) suppresses the development of
Atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
plaques by promoting the death (i.e.
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
) of plaque-bound pro-inflammatory
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s; e) increases the survival of neurons in an inflammation-based model of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
; 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 capillaries.
Arterioles have muscular walls (usually only one to two layers of smooth muscle cells) and are the primar ...
and
capillary
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
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 dorsa ...
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, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
and
hyperalgesia
Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...
) and has been used successfully to block the osteoarthritis pain in dogs.
Gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
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 of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification) ...
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 inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
s such as
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
.
Activation of EP
4 stimulates
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
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 remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
(i.e. cells responsible for bone absorption) to differentiate from precursor cells and is required for
IL-1beta
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
-,
Tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
-, and
basic fibroblast growth factor
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(F ...
-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 language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
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
Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
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 blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
and
ischemic reperfusion injury
Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...
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 kno ...
by the
Cre recombinase
Cre recombinase is a tyrosine recombinase enzyme derived from the P1 bacteriophage. The enzyme uses a topoisomerase I-like mechanism to carry out site specific recombination events. The enzyme (38kDa) is a member of the integrase family of site ...
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. Co ...
, 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 spread 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, then, ...
of human prostate cancer cell
xenograft
Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...
s. 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 spread 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, then, ...
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) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
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. A core component of the cochlea is the Organ of Corti, the sensory org ...
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 corneal tissue as a result of oxygen deprivation. Maintaining avascularity of the corneal stroma is an important aspect of corneal ...
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
Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble l ...
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 respon ...
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, 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 a sufficiently larg ...
(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 characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hip ...
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 vertebral column, also known as the backbone or spine, is part of the axial skeleton. The vertebral column is the defining characteristic of a vertebrate in which the notochord (a flexible rod of uniform composition) found in all chordata, ...
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) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune s ...
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, nails, and related muscle and glands. The major function of this s ...
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 ...
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, 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 does not leave any long-lasti ...
. 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
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
of
Genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varia ...
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 (which may be bloody if inflammation is severe), fever, abdominal distension ...
; 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 protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
, 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 (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
in 5p13.1, a
Gene desert
Gene deserts are regions of the genome that are devoid of protein-coding genes. Gene deserts constitute an estimated 25% of the entire genome, leading to the recent interest in their true functions. Originally believed to contain inessential and ...
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
*
Prostaglandin E2 receptor 1 (EP1)
*
Prostaglandin E2 receptor 2 (EP2)
*
Prostaglandin E2 receptor 3 (EP3)
*
Eicosanoid receptor
Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Acc ...
References
External links
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Further reading
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{{Prostanoidergics
G protein-coupled receptors