Prostaglandin EP4 receptor

Last updated
PTGER4
Identifiers
Aliases PTGER4 , EP4, EP4R, EP4 receptor, prostaglandin E receptor 4
External IDs OMIM: 601586 MGI: 104311 HomoloGene: 20261 GeneCards: PTGER4
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000958

NM_001136079
NM_008965

RefSeq (protein)

NP_000949

NP_001129551
NP_032991

Location (UCSC) Chr 5: 40.68 – 40.69 Mb Chr 15: 5.24 – 5.27 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; [5] it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP4 has been implicated in various physiological and pathological responses in animal models and humans. [6]

Contents

Gene

The PTGER4 gene is located on human chromosome 5p13.1 at position p13.1 (i.e. 5p13.1), contains 7 exons, and codes for a G protein-coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14). [7] [8]

Expression

In humans, mRNA for EP4 has been detected by northern blotting in the heart and small intestine and to lesser extents in lung, kidney, thymus, uterus, dorsal root ganglions, and brain. EP4 protein is found in humans as measured by immunochemistry in pulmonary veins; kidney glomeruli and tunica media of kidney arteries; corpus cavernosum of the penis; carotid artery atherosclerotic plaques; Abdominal aorta aneurysms; corneal endothelium, corneal keratocytes, trabecular cells, ciliary epithelium, conjunctival stromal cells, and iridal stromal cells of the eye; and gingival fibroblasts. [9] [10] [11]

Ligands

Activating ligands

Standard prostanoids have the following relative efficacies in binding to and activating EP4: PGE2>PGF2α=PGI2>PGD2=TXA2. Prostaglandin E1 (PGE1), which has one less double bond than PGE2, has the same binding affinity and potency for EP4, both PGs having high affinity (Ki=3 nM) (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=343). [12] Several synthetic compounds, e.g. 1-hydroxy-PGE1, rivenprost (ONO-4819), OOG-308, ONO-AE1-329, AGN205203, ONO-4819, CP-734,432m AE1-329, SC-19220, SC-51089, and EP4RAG bind to and stimulate EP4 but unlike PGE2 have the advantage of being selective for this receptor over other EP receptors and are relatively resistant to being metabolically degraded. They are in development as drugs for the potential treatment of various diseases including ulcerative colitis, Alzheimer's disease, osteoporosis, and certain cardiovascular diseases. [13]

Inhibiting ligands

Inhibitory receptor antagonists for EP4, including grapiprant (CJ-023,423), ONO-AE3-208, GW627368X, AH23848, and ONO-AE2-227, are in development for possible clinical use as inhibitors of the progression of prostate, breast, colon, and lung cancers. [13]

Mechanism of cell activation

EP4 is classified as a relaxant type of prostaglandin receptor based on its ability, upon activation, to relax the contraction of certain smooth muscle preparations and smooth muscle-containing tissues that have been pre-contracted by stimulation. [6] When bound to PGE2 or other of its agonists, it mobilizes G proteins containing the Gs alpha subunit (i.e. Gαs)-G beta-gammaes (i.e. Gβγ) complex. The complex then dissociate into its Gαs and Gβγ components which act to regulate cell signaling pathways. In particular, Gαs stimulates adenyl cyclase to raise cellular levels of cAMP; cAMP activates PKA, a kinase which in turn activates signaling molecules, in particular, the transcription factor, CREB. Activated CREB stimulates the expression of genes such as c-fos, somatostatin, and corticotropin-releasing hormone that regulate cellular proliferation, cellular differentiation, cellular survival, and angiogenesis. EP4 activation of G proteins also activate PI3K/AKT/mTOR, ERK, and p38 MAPK pathways. Activation of ERK induces expression of EGR1, a transcription factor which controls transcription of genes involved in cellular differentiation and mitogenesis. EP4 also interacts with Prostaglandin E receptor 4-associated protein (EPRAP) to inhibit phosphorylation of the proteasome protein, p105, thereby suppressing a cells ability to activate nuclear factor kappa B, a transcription factor that controls genes coding for cytokines and other elements that regulate inflammation, cell growth, and cell survival (see NF-κB#Structure). The activation of these pathways lead to variety of different types of functional responses depending on cell type, the pathways available in different cell types, and numerous other factors; EP4 activation may therefore have diverse effects on cell function depending on these factors. [6] [14] In many respects, EP4 actions resemble those of another type of another relaxant prostanoid receptor, EP2 but differs from the contractile prostanoid receptors, EP1 and EP3 receptors which mobilize G proteins containing the q-Gβγ complex. [15] [16]

Following its activation, EP4 undergoes homologous desensitization. That is, EP4 becomes insensitive to further activation and internalizes. This effect limits the duration and extent to which EP4 can stimulate cells. Agents which activate certain isoforms of protein kinase C can also desensitize EP4 by a process termed heterologous desensitization. [16]

Functions

Studies using animals genetically engineered to lack EP4 and supplemented by studies examining the actions of EP4 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP4 receptor function found in these studies does not necessarily indicate that in does so in humans since EP receptor functions can vary between species. [14]

Ductus arteriosus

EP4 plays a critical role in postnatal closure of the ductus arteriosus as defined in mice lacking a functional gene for this receptor, i.e. EP4(-/-) mice (see Knockout mouse). About 95% of EP4(-/-) 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 EP4 by PGE2 keeps the ductus open in the fetus; at birth, however, levels of EP4 and PGE2 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 and receptor antagonists, EP2 in mice and, at least in lambs, EP3 may play minor parts in maintaining patency of the ductus. [6] [17] [18] These studies also appear relevant to humans: nonsteroidal anti-inflammatory drugs, particularly indomethacin, are used to reduce prostaglandin production and thereby close the ductus in neonates, infants, and older patients with Patent ductus arteriosus; 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 until corrective surgery can be performed (see Ductus arteriosus#Disorder: Patent ductus arteriosus). [6]

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

Inflammation

Activation of EP4 suppresses the production of IL-12p70 and increases IL-23 thereby promoting development of IL-17-producing Th17 cells, a subset of pro-inflammatory T helper cells 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 cells (i.e. suppressor T cells that modulate the immune system to maintain tolerance to self-antigens and prevent autoimmune disease); b) stimulate Dendritic cells (i.e. antigen-presenting cells located primarily in the skin and mucus membranes) to mature, migrate, and direct the early stage of immune responses; c) inhibit antibody-producing B cells from proliferating; d) suppresses the development of Atherosclerosis plaques by promoting the death (i.e. apoptosis) of plaque-bound pro-inflammatory macrophages; e) increases the survival of neurons in an inflammation-based model of Alzheimer's disease; f) increases local arteriole and capillary 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 neurons from signaling inflammation-induced pain (i.e. allodynia and hyperalgesia) and has been used successfully to block the osteoarthritis pain in dogs. [6] [15] [19] [13]

Gastrointestinal tract

EP4 receptors are highly expressed in the small intestine and colon. Mice lacking this receptor or treated with a selective EP4 antagonist proved to be far more susceptible to the development of dextran sodium sulphate (DSS)-induced colitis and to be protected from developing the colitis by pre-treatment with EP4-selective agonists (ONO-AE1-734 and AGN205203). The DDS-inflicted lesions were associated with defective colon mucosa barrier function along with the overexpression of genes mediating inflammatory responses and under-expression of genes involved in mucosal repair and remodeling. EP4 thus appears to serve anti-inflammatory and protective functions in the colon and agonists of this receptor may be useful for treating inflammatory bowel diseases such as ulcerative colitis. [19] Activation of EP4 stimulates duodenum epithelial cells to secrete bicarbonate (HCO3-) in mice and humans; this response neutralizes the acidic fluid flowing from the stomach thereby contributing to the process of intestinal ulcer healing. Activators of this receptor therefore may useful as anti-ulcer drugs. [14]

Bone

Studies in mice found that the PGE2-EP4 pathway induces osteoclast (i.e. cells responsible for bone absorption) to differentiate from precursor cells and is required for IL-1beta-, Tumor necrosis factor alpha-, and basic fibroblast growth factor-induced osteoclast formation; bone taken from EP4(-/-) mice to re-absorb bone when induced to do so and the infusion of PGE2 into mice failed to stimulate bone absorption. Furthermore, the infusion of selective EP4 agonists into mice stimulated increases in the number of bone osteoclasts and osteoblasts as well as increases in bone density. These studies indicate that the EP4 receptor mediates bone remolding in mice and, it is suggested, other animals including humans. [6]

Heart

In mice, EP4 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. EP4 receptor-depleted mice exhibit more severe cardiac damage in experimental models of myocardial infarction and ischemic reperfusion injury but also develop cardiac hypertrophy with poor cardiac function. [11] Cardiac specific EP4 deficiency using Site-specific recombination by the Cre recombinase method to inactivate EP4 only in cardiac muscle causes a somewhat different form of cardiac disease, dilated cardiomyopathy, that develops within 23–33 weeks after birth in mice. [6] These studies are interpreted as indicating that EP4 plays both protective and damaging roles in the heart with the protective effects of EP4 due at least in part to its ability to suppress inflammation.

Lipid metabolism

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

Cancer

The EP4 receptor is over-expressed in human prostate cancer tissue and a selective EP4-receptor antagonist inhibits the growth and metastasis of human prostate cancer cell xenografts. An EP4 receptor antagonist as well EP4 Gene knockdown inhibit the in vitro proliferation and invasiveness of human breast cancer cells. And, gene knockdown of EP4 inhibit the metastasis of murine breast cancer cells in a mouse model of induced breast cancer. PGE2 stimulates the in vitro growth of human non-small cell lung cancer while an antagonist of EP4 or EP4 gene knockdown inhibits this growth. These results indicate that the stimulation of EP4 promotes the growth of various types of cancer cells and therefore may play a role in the progression of certain types of human cancer. [13]

Hearing

EP44 receptors are expressed in the cochlea of the inner ear. Pre- and post-treatment of guinea pigs with an EP4 agonist significantly attenuated threshold shifts of auditory brain stem responses and significantly reduced the loss of outer hair cells caused by prior noise exposure. These findings indicate that EP4 is involved in mechanisms for prostaglandin E(1) actions on the cochlea, and local EP4 agonist treatment may be a means for attenuating noise-induced hearing lose. [21] [6]

Eye

A selective EP4 antagonists significantly reduced corneal neovascularization in rats caused by oxygen-induced retinopathy or laser-induced choroidal neovascularization. This result suggests that EP4 activation contributes to corneal neovascularization and that EP4 antagonists may be useful for treating neovascular eye disease. [6]

Clinical significance

Translational research

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

Genomic Studies

Single nucleotide polymorphism (SNP) A/G variant rs10440635 [24] close to the PTGER4 gene on human chromosome 5 has been associated with an increased incidence of Ankylosing spondylitis 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 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. [25] [26]

The GG genotype at -1254G>A in PTGER4 is associated with the non-steroidal anti-inflammatory drug (NSAID)-exacerbated cutaneous disease (NECD). NECD is a non-allergic hypersensitivity reaction involving the acute development of wheals and angioedema in response to NSAID consumption in individuals with a history of chronic urticarial. The G allele at the -1254 position leads to lower PTGER4 gene promoter function, lower levels of EP4, and presumably thereby less of the anti-inflammatory effects of EP4. [27]

Several PTGER4 gene variations have been associated with inflammatory bowel disease: a) Meta-analysis of Genome-wide association studies found that SNP variant rs11742570 [28] containing a C/T single-nucleotide variation in PTGER4 is associated with an increased incidence of Crohn's disease; b) rs4495224, [29] an A/C SNP variant, and rs7720838, [30] both of which are projected to be binding sites in PTERG4 for the transcription factor, NF-κB, 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 in 5p13.1, a Gene desert close to PTGER4, correlate with the expression levels of EP4 as well as with the development of Crohn's disease. [27]

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

See also

Related Research Articles

<span class="mw-page-title-main">Prostaglandin</span> Group of physiologically active lipid compounds

Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

<span class="mw-page-title-main">Ductus arteriosus</span> Blood vessel connecting the pulmonary artery to the proximal descending aorta

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 most of the blood from the right ventricle to bypass the fetus's fluid-filled non-functioning lungs. Upon closure at birth, it becomes the ligamentum arteriosum.

Prostaglandin E<sub>2</sub> Chemical compound

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 in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.

<span class="mw-page-title-main">Enprostil</span> Chemical compound

Enprostil is a synthetic prostaglandin designed to resemble dinoprostone. Enprostil was found to be a highly potent inhibitor of gastric HCl secretion. It is an analog of prostaglandin E2 but unlike this prostaglandin, which binds to and activates all four cellular receptors viz., EP1, EP2, EP3, and EP4 receptors, enprostil is a more selective receptor agonist in that it binds to and activates primarily the EP3 receptor. Consequently, enprostil is expected to have a narrower range of actions that may avoid some of the unwanted side-effects and toxicities of prostaglandin E2. A prospective multicenter randomized controlled trial conducted in Japan found combining enprostil with cimetidine was more effective than cimetidine alone in treating gastric ulcer.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

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. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

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,, PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. They are named based on the prostanoid to which they preferentially bind and respond, e.g. the receptor responsive to PGI2 at lower concentrations than any other prostanoid is named the Prostacyclin receptor (IP). One exception to this rule is the receptor for thromboxane A2 (TP) which binds and responds to PGH2 and TXA2 equally well.

Prostaglandin DP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

The Prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), is primarily a receptor for prostaglandin D2 (PGD2). The receptor is a member of the Prostaglandin receptors belonging to the Subfamily A14 of rhodopsin-like receptors. Activation of DP1 by PGD2 or other cognate receptor ligands is associated with a variety of physiological and pathological responses in animal models.

Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.

Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

Prostaglandin EP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 1 (EP1) is a 42kDa prostaglandin receptor encoded by the PTGER1 gene. EP1 is one of four identified EP receptors, EP1, EP2, EP3, and EP4 which bind with and mediate cellular responses principally to prostaglandin E2) (PGE2) and also but generally with lesser affinity and responsiveness to certain other prostanoids (see Prostaglandin receptors). Animal model studies have implicated EP1 in various physiological and pathological responses. However, key differences in the distribution of EP1 between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease.

Prostaglandin EP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

Prostaglandin EP<sub>3</sub> receptor Protein-coding gene in the species Homo sapiens

Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

<span class="mw-page-title-main">Prostaglandin F receptor</span> Protein-coding gene in the species Homo sapiens

Prostaglandin F receptor (FP) is a receptor belonging to the prostaglandin (PG) group of receptors. FP binds to and mediates the biological actions of Prostaglandin F (PGF). It is encoded in humans by the PTGFR gene.

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

The Prostacyclin receptor, also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.

<span class="mw-page-title-main">Sulprostone</span> Chemical compound

Sulprostone is an analogue of prostaglandin E2 (PGE2) that has oxytocic activity in assays of rat kidney cells and tissues. There are four known receptors which mediate various but often different cellular and tissue responses to PGE2: prostaglandin EP1 receptor, prostaglandin EP2 receptor, prostaglandin EP3 receptor, and prostaglandin EP4 receptor. Sulprosotone binds to and activates the prostaglandin EP3 receptor with far greater efficacy than the other PGE2 receptors and also has the advantage of being relatively resistant, compared with PGE2, to becoming metabolically degraded. It is listed as a comparatively weak receptor agonist of the prostaglandin EP1 receptor. In all events, this as well as other potent synthetic EP3 receptor antagonists have the realized or potential ability to promote the beneficial effects of prostaglandin EP3 receptor activation.

The prostaglandin D2 (PGD2) receptors are G protein-coupled receptors that bind and are activated by prostaglandin D2. Also known as PTGDR or DP receptors, they are important for various functions of the nervous system and inflammation. They include the following proteins:

The prostaglandin E2 (PGE2) receptors are G protein-coupled receptors that bind and are activated by prostaglandin E2. They are members of the prostaglandin receptors class of receptors and include the following Protein isoforms:

<span class="mw-page-title-main">Grapiprant</span> NSAID anti-inflammatory veterinary drug

Grapiprant is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA's Center for Veterinary Medicine and was categorized as a non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000171522 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039942 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "PTGER3 prostaglandin e receptor 3 [Homo sapiens (Human)] - Gene - NCBI". Archived from the original on 2016-02-26. Retrieved 2017-01-24.
  6. 1 2 3 4 5 6 7 8 9 10 11 Woodward DF, Jones RL, Narumiya S (September 2011). "International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress". Pharmacological Reviews. 63 (3): 471–538. doi: 10.1124/pr.110.003517 . PMID   21752876.
  7. "PTGER4 prostaglandin e receptor 4 [Homo sapiens (Human)] - Gene - NCBI". Archived from the original on 2017-02-11. Retrieved 2017-02-06.
  8. "Entrez Gene: PTGER4 prostaglandin E receptor 4 (subtype EP4)". Archived from the original on 2010-12-05.
  9. "EP4 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org. Archived from the original on 2 January 2018. Retrieved 6 May 2018.
  10. Ichikawa A, Sugimoto Y, Tanaka S (2010). "Molecular biology of histidine decarboxylase and prostaglandin receptors". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 86 (8): 848–66. Bibcode:2010PJAB...86..848I. doi:10.2183/pjab.86.848. PMC   3037517 . PMID   20948178.
  11. 1 2 3 Pang L, Cai Y, Tang EH, Irwin MG, Ma H, Xia Z (2016). "Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy". Journal of Diabetes Research. 2016: 1324347. doi: 10.1155/2016/1324347 . PMC   4846751 . PMID   27190998.
  12. Narumiya S, Sugimoto Y, Ushikubi F (October 1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. doi:10.1152/physrev.1999.79.4.1193. PMID   10508233. S2CID   7766467.
  13. 1 2 3 4 5 6 Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I (January 2017). "Structural features of subtype-selective EP receptor modulators". Drug Discovery Today. 22 (1): 57–71. doi: 10.1016/j.drudis.2016.08.003 . PMID   27506873.
  14. 1 2 3 Moreno JJ (February 2017). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis". European Journal of Pharmacology. 796: 7–19. doi:10.1016/j.ejphar.2016.12.004. PMID   27940058. S2CID   1513449.
  15. 1 2 Kalinski P (January 2012). "Regulation of immune responses by prostaglandin E2". Journal of Immunology. 188 (1): 21–8. doi:10.4049/jimmunol.1101029. PMC   3249979 . PMID   22187483.
  16. 1 2 Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D (2014). "Cyclooxygenase pathways". Acta Biochimica Polonica. 61 (4): 639–49. doi: 10.18388/abp.2014_1825 . PMID   25343148.
  17. Ushikubi F, Sugimoto Y, Ichikawa A, Narumiya S (August 2000). "Roles of prostanoids revealed from studies using mice lacking specific prostanoid receptors". Japanese Journal of Pharmacology. 83 (4): 279–85. doi: 10.1254/jjp.83.279 . PMID   11001172.
  18. Bouayad A, Kajino H, Waleh N, Fouron JC, Andelfinger G, Varma DR, Skoll A, Vazquez A, Gobeil F, Clyman RI, Chemtob S (May 2001). "Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus". American Journal of Physiology. Heart and Circulatory Physiology. 280 (5): H2342-9. doi: 10.1152/ajpheart.2001.280.5.H2342 . PMID   11299240. S2CID   32049750.
  19. 1 2 Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y (December 2014). "Prostanoid receptors and acute inflammation in skin". Biochimie. 107 Pt A: 78–81. doi:10.1016/j.biochi.2014.08.010. PMID   25179301.
  20. Cai Y, Ying F, Song E, Wang Y, Xu A, Vanhoutte PM, Tang EH (December 2015). "Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance". FASEB Journal. 29 (12): 4924–36. doi:10.1096/fj.15-274597. PMID   26271253. S2CID   28363263.
  21. Hori R, Nakagawa T, Sugimoto Y, Sakamoto T, Yamamoto N, Hamaguchi K, Ito J (June 2009). "Prostaglandin E receptor subtype EP4 agonist protects cochleae against noise-induced trauma". Neuroscience. 160 (4): 813–9. doi:10.1016/j.neuroscience.2009.03.014. hdl: 2433/120543 . PMID   19303430. S2CID   23372528.
  22. De Vito V, Salvadori M, Poapolathep A, Owen H, Rychshanova R, Giorgi M (October 2017). "Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan-induced inflammatory pain model in the rabbit". Journal of Veterinary Pharmacology and Therapeutics. 40 (5): 468–475. doi:10.1111/jvp.12380. PMID   27925221. S2CID   4170611.
  23. Okumura Y, Yamagishi T, Nukui S, Nakao K (March 2017). "Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist". Bioorganic & Medicinal Chemistry Letters. 27 (5): 1186–1192. doi:10.1016/j.bmcl.2017.01.067. PMID   28169162.
  24. snpdev. "Reference SNP (refSNP) Cluster Report: rs10440635". www.ncbi.nlm.nih.gov. Archived from the original on 18 February 2017. Retrieved 6 May 2018.
  25. Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Oppermann U, Opperman U, Dilthey A, Pirinen M, Stone MA, Appleton L, Moutsianas L, Moutsianis L, Leslie S, Wordsworth T, Kenna TJ, Karaderi T, Thomas GP, Ward MM, Weisman MH, Farrar C, Bradbury LA, Danoy P, Inman RD, Maksymowych W, Gladman D, Rahman P, Morgan A, Marzo-Ortega H, Bowness P, Gaffney K, Gaston JS, Smith M, Bruges-Armas J, Couto AR, Sorrentino R, Paladini F, Ferreira MA, Xu H, Liu Y, Jiang L, Lopez-Larrea C, Díaz-Peña R, López-Vázquez A, Zayats T, Band G, Bellenguez C, Blackburn H, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Freeman C, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jankowski J, Jayakumar A, Langford C, Liddle J, Markus HS, Mathew CG, McCann OT, McCarthy MI, Palmer CN, Peltonen L, Plomin R, Potter SC, Rautanen A, Ravindrarajah R, Ricketts M, Samani N, Sawcer SJ, Strange A, Trembath RC, Viswanathan AC, Waller M, Weston P, Whittaker P, Widaa S, Wood NW, McVean G, Reveille JD, Wordsworth BP, Brown MA, Donnelly P (July 2011). "Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility". Nature Genetics. 43 (8): 761–7. doi:10.1038/ng.873. PMC   3640413 . PMID   21743469.
  26. Haroon N (June 2015). "Ankylosis in ankylosing spondylitis: current concepts". Clinical Rheumatology. 34 (6): 1003–7. doi:10.1007/s10067-015-2956-4. PMID   25935456. S2CID   25930196.
  27. 1 2 3 Cornejo-García JA, Perkins JR, Jurado-Escobar R, García-Martín E, Agúndez JA, Viguera E, Pérez-Sánchez N, Blanca-López N (2016). "Pharmacogenomics of Prostaglandin and Leukotriene Receptors". Frontiers in Pharmacology. 7: 316. doi: 10.3389/fphar.2016.00316 . PMC   5030812 . PMID   27708579.
  28. "No items found - Gene - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 19 February 2017. Retrieved 6 May 2018.
  29. "No items found - Gene - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 4 March 2017. Retrieved 6 May 2018.
  30. "PTGER4 prostaglandin e receptor 4 [Homo sapiens (Human)] - Gene - NCBI". Archived from the original on 2018-05-06. Retrieved 2017-02-19.
  31. "No items found - Gene - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 4 March 2017. Retrieved 6 May 2018.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.