Prostaglandin EP3 receptor (EP3, 53kDa), is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; [5] 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). [6] EP has been implicated in various physiological and pathological responses. [7]
The PTGER3 gene is located on human chromosome 1 at position p31.1 (i.e. 1p31.1), contains 10 exons, and codes for a G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14). PTGER3 codes for at least 8 different isoforms in humans, i.e. PTGER3-1 to PGGER3-8 (i.e., EP3-1, EP3-2, EP3-3, EP3-4, EP3-5, EP3-6, EP3-7, and EP3-8), while Ptger3 codes for at least 3 isoforms in mice, Ptger1-Ptger3 (i.e. Ep3-α, Ep3-β, and Ep3-γ). These isoforms are variants made by Alternative splicing conducted at the 5'-end of DNA to form proteins that vary at or near their C-terminus. [5] [8] [9] Since these isoforms different in their tissue expressions as well as the signaling pathways which they activate, they may vary in the functions that they perform. [10] Further studies are needed to examine functional differences among these isoforms.
EP3 is widely distributed in humans. Its protein and/or mRNA is expressed in kidney (i.e. glomeruli, Tamm-Horsfall protein negative late distal convoluted tubules, connecting segments, cortical and medullary collecting ducts, media and endothelial cells of arteries and arterioles); stomach (vascular smooth muscle and gastric fundus mucosal cells); thalamus (anterior, ventromedial, laterodorsal, paraventricular and central medial nuclei); intestinal mucosal epithelia at the apex of crypts; myometrium (stromal cells, endothelial cells, and, in pregnancy, placenta, chorion, and amnion); mouth gingival fibroblasts; and eye (corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, and conjunctival and iridal stroma cells, and retinal Müller cells). [11]
Standard prostanoids have the following relative efficacies in binding to and activating EP3: PGE2>PGF2α=PGI2>PGD2=TXA2. Prrostglandin E1 (PGE1), which has one less double bond than PGE2, has the same binding affinity and potency for EP3 as PGE2. [11] PGE2 has extreme high affinity (dissociation constant Kd=0.3 nM) for EP3. Several synthetic compounds, e.g. sulprostone, SC-46275, MB-28767, and ONO-AE-248, bind to and stimulate with high potency EP3 but unlike PGE2 have the advantage of being highly 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 stomach ulcers in humans. [12]
Numerous synthetic compounds have been found to be highly selective in binding to but not stimulating EP3. These Receptor antagonist DG-O41, L798,106, and ONO-AE3-240, block EP3 from responding to PGE2 or other agonists of this receptor, including Sulprostone, ONO-AE-248 and TEI-3356. They are in development primarily as anti-thrombotics, i.e. drugs to treat pathological blood clotting in humans. [12]
EP3 is classified as an inhibitory type of prostanoid receptor based on its ability, upon activation, to inhibit the activation of adenylyl cyclase stimulated by relaxant types of prostanoid receptors viz., prostaglandin DP, E2, and E4 receptors (see Prostaglandin receptors). When initially bound to PGE2 or other of its agonists, it mobilizes G proteins containing various types of G proteins, depending upon the particular EP3 isoform: EP3α and EP3β isoforms activate Gi alpha subunit (i.e. Gαi)-G beta-gamma complexes (i.e. Gαi)-Gβγ) complexes) as well as Gα12-Gβγ complexes while the EP3γ isoform activates in addition to and the Gαi- Gβγ complexes Gαi- Gβγ complexes. [13] (G protein linkages for the other EP3 isoforms have not been defined.) In consequence, complexes dissociate into Gαi, Gα12, Gs and Gβγ components which proceed to activate cell signaling pathways that lead functional responses viz., pathways that activate phospholipase C to convert cellular phospholipids to diacylglycerol which promotes the activation of certain isoforms of protein kinase C, pathways that elevated cellular cytosolic Ca2+ which thereby regulate Ca2+-sensitive cell signaling molecules, and pathways that inhibit adenylyl cyclase which thereby lowers cellular levels of cyclic adenosine monophosphate (cAMP) to reduce the activity of cAMP-dependent signaling molecules. [13]
Studies using animals genetically engineered to lack EP3 and supplemented by studies examining the actions of EP3 receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP3 receptor function found in these studies does not necessarily indicate that in does do in humans. For example, EP3 receptor activation promotes duodenal secretion in mice; this function is mediated by EP4 receptor activation in humans. [13] EP receptor functions can vary with species and most of the functional studies cited here have not translated their animal and tissue models to humans.
The secretion of HCO−
3 (bicarbonate anion) from Brunner's glands of the duodenum serves to neutralize the highly acidified digestive products released from the stomach and thereby prevents ulcerative damage to the small intestine. Activation of EP3 and EP4 receptors in mice stimulates this secretion but in humans activation of EP4, not EP3, appears responsible for this secretion. [13] These two prostanoid receptors also stimulate intestinal mucous secretion, a function which may also act to reduce acidic damage to the duodenum. [14]
EP3-deficient mice as well as mice selectively deleted of EP3 expression in the brain's median preoptic nucleus fail to develop fever in response to endotoxins (i.e. bacteria-derived lipopolysaccharide) or the host-derived regulator of body temperature, IL-1β. The ability of endotoxins and IL-1β but not that of PGE2 to trigger fever is blocked by inhibitors of nitric oxide and PG2. EP3-deficient mice exhibit normal febrile responses to stress, interleukin-8, and macrophage inflammatory protein-1beta (MIP-1β). It is suggested that these findings indicate that a) activation of the EP3 receptor suppresses the inhibitory tone that the preoptic hypothalamus has on thermogenic effector cells in the brain; b) endotoxin and IL-1β simulate the production of nitric oxide which in turn causes the production of PGE2 and thereby the EP3-dependent fever-producing; c) other factors such as stress, interleukin 8, and MIP-1β trigger fever independently of EP3; and d) inhibition of the PGE2-EP3 pathway underlies the ability of aspirin and other Nonsteroidal anti-inflammatory drugs to reduce fever caused by inflammation in animals and, possibly, humans. [15] [16]
In a mouse model of ovalbumin-induced asthma, a selective EP3 agonist reduced airway cellularity, mucus, and bronchoconstriction responses to methacholine. In this model, EP3-deficient mice, upon ovalbumin challenge, exhibited worsened allergic inflammation as measured by increased airway eosinophils, neutrophils, lymphocytes, and pro-allergic cytokines (i.e. interleukin 4, interleukin 5, and interleukin 13) as compared to wild type mice. [7] [17] EP3 receptor-deficient mice and/or wild type mice treated with an EP3 receptor agonist are similarly protected from allergic responses in models of allergic conjunctivitis and contact hypersensitivity. [18] Thus, EP3 appears to serve an important role in reducing allergic reactivity at least in mice.
Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that PGE2 operates through EP3 to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716 [19] ), has been associated with ACE inhibitor-induce cough in humans. [20] [21] The use of EP3 receptor antagonists may warrant study for the treatment of chronic cough in humans. [22]
Activation of EP3 receptors contracts vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, rodent and human pulmonary artery, and murine renal and brain vasculature. Mice depleted of EP3 are partially protected from brain injury consequential to experimentally induced cerebral ischemia. Furthermore, rodent studies indicate that agonist-induced activation of EP3 in the brain by intra-cerebroventricular injection of PGE2 or selective EP3 agonist cause hypertension; a highly selective EP3 receptor antagonist blocked this PGE2-induced response. These studies, which examine a sympatho-excitatory response (i.e. responses wherein brain excitation such as stroke raises blood pressure) suggest that certain hypertension responses in humans are mediated, at least in part, by EP3. [23]
Model studies indicate that PG2 (but not specific antigens or IgE cross-linkage) stimulates mouse and human mast cells to release histamine by an EP3-dependent mechanism. Furthermore, EP3-deficient mice fail to develop increased capillary permeability and tissue swelling in response to EP3 receptor agonists and the metabolic precursor to PGE2, arachidonic acid. It is suggested, based on these and other less direct studies, that PGE2-EP3 signaling may be responsible for the skin swelling and edema provoked by topical 5-aminolaevulinic acid photodynamic therapy, contact with chemical irritants, infection with pathogens, and various skin disorders in humans. [24] [25]
Activation of EP3 receptors on the blood platelets of mice, monkeys, and humans enhances their aggregation, degranulation, and blood clot-promoting responsiveness to a wide array of physiological (e.g. thrombin) and pathological (e.g. atheromatous plaques. (In contrast, activation of either the EP2 or EP3 receptor inhibits platelet activation) Inhibition of EP3 with the selective EP3 receptor antagonist, DG-041, has been shown to prevent blood clotting but not to alter hemostasis or blood loss in mice and in inhibit platelet activation responses in human whole blood while not prolonging bleeding times when given to human volunteers. The drug has been proposed to be of potential clinical use for the prevention of blood clotting while causing little or no bleeding tendencies. [26] [27]
EP3 deficient mice exhibit significant reductions in: hyperalgesic writhing (i.e. squirming) responses to acetic acid administration; acute but not chronic Herpes simplex infection-induced pain; and HIV-1 Envelope glycoprotein GP120 intrathecal injection-induced tactile allodynia. Furthermore, a selective EP3 agonist, ONO-AE-248, induces hyperalgesia pain in wild type but not EP3-deficient mice. [28] [29] [30] While pain perception is a complex phenomenon involving multiple causes and multiple receptors including EP2, EP1, LTB4, bradykinin, nerve growth factor, and other receptors, these studies indicate that EP3 receptors contribute to the perception of at least certain types of pain in mice and may also do so in humans.
Studies of the direct effects of EP3 receptor activation on cancer in animal and tissue models give contradictory results suggesting that this receptor does not play an important role in Carcinogenesis. However, some studies suggest an indirect pro-carcinogenic function for the EP3 receptor: The growth and metastasis of implanted Lewis lung carcinoma cells, a mouse lung cancer cell line, is suppressed in EP3 receptor deficient mice. This effect was associated with a reduction in the levels of Vascular endothelial growth factor and matrix metalloproteinase-9 expression in the tumor's stroma; expression of the pro-lymphangiogenic growth factor VEGF-C and its receptor, VEGFR3; and a tumor-associated angiogenesis and lymphangiogenesis. [31]
Many drugs that act on EP3 and, often, other prostaglandin receptors, are in clinical use. A partial list of these includes:
Other drugs are in various stages of clinical development or have been proposed to be tested for clinical development. A sampling of these includes:
The single nucleotide polymorphism (SNP) in the PTGER3, rs977214 A/G variant [36] has been associated with an increase in pre-term births in two populations of European ancestry; the SNP variant -1709T>A in PTGER3 has been associated with aspirin-exacerbated respiratory disease in a Korean population; and 6 SNP variants have been associated with development of the Steven Johnson syndrome and its more severe form, toxic epidermal necrolysis, in a Japanese population. [37] [38]
Prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids that have 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.
Estrogen receptors (ERs) are proteins found in cells that function as receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen receptors, namely ERα and ERβ, which belong to the nuclear receptor family. The second class consists of membrane estrogen receptors (mERs), such as GPER (GPR30), ER-X, and Gq-mER, which are primarily G protein-coupled receptors. This article focuses on the nuclear estrogen receptors.
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.
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.
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.
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.
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.
Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.
Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; 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.
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 prostglandin 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 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 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 F receptor (FP) is a receptor belonging to the prostaglandin (PG) group of receptors. FP binds to and mediates the biological actions of prostaglandin F2α (PGF2α). It is encoded in humans by the PTGFR gene.
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.
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:
Grapiprant, sold under the brand name Galliprant, 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.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
