EP4 receptor

Target id: 343

Nomenclature: EP4 receptor

Family: Prostanoid receptors

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Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 488 5p13.1 PTGER4 prostaglandin E receptor 4 5,8
Mouse 7 513 15 A1 Ptger4 prostaglandin E receptor 4 (subtype EP4) 42
Rat 7 488 2q16 Ptger4 prostaglandin E receptor 4 14,100
Previous and Unofficial Names
EP2 [5,8,37,42,100] | PGE receptor EP4 subtype | prostanoid EP4 receptor
Database Links
Specialist databases
GPCRDB pe2r4_human (Hs), pe2r4_mouse (Mm), pe2r4_rat (Rn)
Other databases
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
PGD2
PGE2
PGF
PGI2
Comments: PGE2 is the principal endogenous agonist
Potency order of endogenous ligands
PGE2 = PGE1 > PGF, PGI2 > PGD2, thromboxane A2

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]PGE2 Rn Full agonist 9.0 pKd 14
pKd 9.0 [14]
PGE2 Mm Full agonist 8.6 pKd 54
pKd 8.6 (Kd 2.5x10-9 M) [54]
[3H]PGE2 Hs Full agonist 7.6 – 9.5 pKd 1,21,115-116
pKd 7.6 – 9.5 (Kd 2.4x10-8 – 3x10-10 M) [1,21,115-116]
L902688 Hs Agonist 9.4 pKi 127
pKi 9.4 (Ki 3.8x10-10 M) [127]
PGF Hs Full agonist 9.1 – 9.5 pKi 1,21,107
pKi 9.1 – 9.5 (Ki 8x10-10 – 3.2x10-10 M) [1,21,107]
PGE1 Rn Full agonist 9.2 pKi 14
pKi 9.2 [14]
rivenprost Mm Full agonist 9.2 pKi 125
pKi 9.2 [125]
ONO-AE1-437 Mm Agonist 9.1 pKi 70
pKi 9.1 (Ki 7.1x10-10 M) [70]
PGE2 Rn Full agonist 9.0 pKi 14
pKi 9.0 [14]
11-deoxy-PGE2 Rn Full agonist 9.0 pKi 14
pKi 9.0 [14]
TCS 2510 Hs Agonist 8.9 pKi 127
pKi 8.9 (Ki 1.2x10-9 M) [127]
11-deoxy-PGE1 Hs Full agonist 8.9 pKi 21
pKi 8.9 [21]
PGD2 Hs Full agonist 8.7 – 9.0 pKi 21,107
pKi 8.7 – 9.0 (Ki 2x10-9 – 1x10-9 M) [21,107]
PGE1 Hs Full agonist 8.8 pKi 21
pKi 8.8 (Ki 1.58x10-9 M) [21]
PGE1 Mm Full agonist 8.7 pKi 54
pKi 8.7 [54]
PGE2 Mm Full agonist 8.5 – 8.7 pKi 54,108
pKi 8.5 – 8.7 (Ki 3x10-9 – 2x10-9 M) [54,108]
PGE2 Hs Full agonist 8.1 – 9.1 pKi 1,21,79,107,116
pKi 8.1 – 9.1 (Ki 7.94x10-9 – 7.94x10-10 M) [1,21,79,107,116]
13,14-dihydro-PGE1 Hs Full agonist 8.5 pKi 21
pKi 8.5 [21]
ONO-AE1-329 Mm Full agonist 8.0 pKi 108
pKi 8.0 (Ki 1x10-8 M) [108]
MB-28767 Hs Full agonist 7.5 – 8.0 pKi 1,107
pKi 7.5 – 8.0 [1,107]
MB-28767 Rn Full agonist 7.6 pKi 14
pKi 7.6 [14]
11-deoxy-PGE1 Mm Full agonist 7.6 pKi 54
pKi 7.6 [54]
misoprostol (free acid form) Hs Full agonist 7.6 pKi 1
pKi 7.6 [1]
19(R)-OH-PGE2 Rn Full agonist 7.5 pKi 14
pKi 7.5 [14]
cicaprost Hs Full agonist 7.4 pKi 1
pKi 7.4 [1]
enprostil Hs Full agonist 7.4 pKi 21
pKi 7.4 [21]
16,16-dimethyl-PGE2 Mm Full agonist 7.4 pKi 54
pKi 7.4 [54]
1-OH-PGE1 Mm Full agonist 6.7 pKi 54
pKi 6.7 [54]
carbacyclin Hs Full agonist 6.5 pKi 1
pKi 6.5 [1]
MB-28767 Mm Full agonist 6.3 pKi 54
pKi 6.3 (Ki 5x10-7 M) [54]
PGF Rn Full agonist 6.2 pKi 14
pKi 6.2 [14]
treprostinil Hs Agonist 6.1 pKi 115
pKi 6.1 (Ki 8x10-7 M) [115]
PGD2 Rn Full agonist 5.9 pKi 14
pKi 5.9 [14]
U46619 Hs Full agonist 5.7 pKi 1
pKi 5.7 [1]
iloprost Hs Full agonist 4.6 – 6.7 pKi 1,21,115
pKi 4.6 – 6.7 (Ki 2.3x10-5 – 2.1x10-7 M) [1,21,115]
U46619 Rn Full agonist 5.6 pKi 14
pKi 5.6 [14]
carbacyclin Mm Full agonist 5.6 pKi 54
pKi 5.6 [54]
iloprost Mm Full agonist 5.6 pKi 54
pKi 5.6 [54]
MRE-269 Hs Agonist 5.3 pKi 59
pKi 5.3 (Ki 4.9x10-6 M) [59]
misoprostol (methyl ester) Hs Full agonist 5.3 pKi 1
pKi 5.3 [1]
beraprost Hs Agonist 5.1 pKi 59
pKi 5.1 (Ki 7.2x10-6 M) [59]
PGI2 Hs Full agonist 5.1 pKi 21
pKi 5.1 [21]
butaprost (free acid form) Rn Full agonist 4.8 pKi 14
pKi 4.8 [14]
butaprost (free acid form) Hs Full agonist 4.7 pKi 1
pKi 4.7 [1]
PGE1 Hs Full agonist 9.5 pEC50 60
pEC50 9.5 (EC50 3.1x10-10 M) [60]
11-deoxy-PGE1 Hs Agonist 9.3 pEC50 60
pEC50 9.3 (EC50 4.7x10-10 M) [60]
L902688 Hs Agonist 8.1 – 10.3 pEC50 32,60
pEC50 8.1 – 10.3 (EC50 9x10-9 – 5x10-11 M) [32,60]
CP734432 Hs Agonist 9.0 pEC50 91
pEC50 9.0 (EC50 1x10-9 M) [91]
PGD2 Hs Full agonist 8.8 pEC50 60
pEC50 8.8 (EC50 1.7x10-9 M) [60]
MB-28767 Hs Full agonist 7.8 pEC50 60
pEC50 7.8 (EC50 1.77x10-8 M) [60]
ONO-AE1-329 Hs Full agonist 7.7 – 7.8 pEC50 31-32
pEC50 7.7 – 7.8 (EC50 2.2x10-8 – 1.6x10-8 M) [31-32]
treprostinil Hs Agonist 6.7 pEC50 115
pEC50 6.7 (EC50 2x10-7 M) [115]
iloprost Hs Full agonist 6.4 pEC50 115
pEC50 6.4 (EC50 4x10-7 M) [115]
PGE2 Hs Full agonist 6.1 pEC50 60
pEC50 6.1 (EC50 9x10-7 M) [60]
PGF Hs Full agonist 6.1 pEC50 60
pEC50 6.1 (EC50 9x10-7 M) [60]
CP734432 Hs Full agonist 8.7 pIC50 91
pIC50 8.7 (IC50 2x10-9 M) [91]
View species-specific agonist tables
Agonist Comments
ONO-AE1-329, TCS-2510 and L-902688 are useful selective EP4 agonists.
Analogues with optimized EP2 / EP4 agonism have been recently developed [51].
ONO-4232, a selective EP4 agonist is in Phase I clinical trials in acute heart failure [114].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
TG6-129 Hs Antagonist 5.4 pKB 36
pKB 5.4 (KB 3.9x10-6 M) [36]
ER819762 Hs Antagonist 9.3 pKi 13
pKi 9.3 (Ki 5.6x10-10 M) [13]
MK-2894 Hs Antagonist 9.3 pKi 1,13,20
pKi 9.3 (Ki 5.6x10-10 M) [1,13,20]
MF 498 Hs Antagonist 9.1 pKi 20
pKi 9.1 (Ki 7x10-10 M) [20]
ONO-AE3-208 Mm Antagonist 8.9 pKi 49
pKi 8.9 [49]
evatanepag Hs Antagonist 8.6 pKi 74
pKi 8.6 (Ki 2.51x10-9 M) [74]
ONO-AE2-227 Mm Antagonist 8.6 pKi 76
pKi 8.6 (Ki 2.7x10-9 M) [76]
CJ-042794 Hs Antagonist 8.5 pKi 73
pKi 8.5 (Ki 3.1x10-9 M) [73]
EP4A Hs Antagonist 7.6 – 8.5 pKi 65,127
pKi 7.6 – 8.5 [65,127]
BGC201531 Hs Antagonist 7.9 pKi 67
pKi 7.9 (Ki 1.26x10-8 M) [67]
grapiprant Hs Antagonist 7.9 pKi 79
pKi 7.9 (Ki 1.3x10-8 M) [79]
EP4A Rn Antagonist 7.5 pKi 65
pKi 7.5 [65]
ONO-AE3-240 Mm Antagonist 7.2 pKi 4
pKi 7.2 (Ki 5.8x10-8 M) [4]
GW 627368 Hs Antagonist 7.0 – 7.1 pKi 116-117
pKi 7.0 – 7.1 (Ki 1x10-7 – 7.94x10-8 M) [116-117]
AH23848 Hs Antagonist 4.9 – 5.6 pKi 1,21
pKi 4.9 – 5.6 [1,21]
pKi 5.0 [1]
AH23848 Rn Antagonist 5.1 pKi 14
pKi 5.1 [14]
AH23848 (racemic) Rn Antagonist 5.0 pKi 14
pKi 5.0 [14]
ER819762 Hs Antagonist 7.2 pIC50 18
pIC50 7.2 (IC50 7x10-8 M) [18]
View species-specific antagonist tables
Antagonist Comments
The archetypal EP4 antagonist AH-23848 has been superseded by more potent and selective agents: CJ-023423, GW-627368, L-161982, ONO-AE3-208.
The NH group in antagonists containing an acyl-sulphonamido moiety (e.g. GW-627368) is acidic.
Allosteric Modulators
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
THG213.29 Rn Negative 5.5 pIC50 61
pIC50 5.5 (IC50 3x10-6 M) [61]
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  81
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Other - See Comments
Comments:  A second EP4 signaling pathway is PI3K dependent via G protein Gi activation.
References:  33,35,95,98
Tissue Distribution
Abdominal aorta aneurysm.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR, Western blotting.
References:  122
Mouth: gingival fibroblasts.
Species:  Human
Technique:  RT-PCR.
References:  85
Eye: corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, conjunctival and iridal stroma cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  101
Kidney: glomeruli, media of arteries.
Species:  Human
Technique:  Immunohistochemistry, Western blotting.
References:  72
Penis: corpus cavernosum.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  55
Pulmonary veins.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR.
References:  32
Cultured mastocyte.
Species:  Human
Technique:  RT-PCR.
References:  28
Carotid atherosclerotic plaques.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR, Western blotting.
References:  19,109
Small intestine > lung, kidney, thymus, uterus, brain.
Species:  Human
Technique:  Northern blotting.
References:  8
Kidney: glomerulus.
Species:  Human
Technique:  in situ hybridization.
References:  15
Gastrointestinal tract: small intestine and colon (intestinal mucosal layer), stomach (gastric mucosal layer containing epithelial cells).
Species:  Rat
Technique:  Northern blotting.
References:  23
Kidney: outer medulla, papilla > cortex.
Species:  Rat
Technique:  RNase protection assay.
References:  46
Forebrain: meninges, hippocampus (dentate gyrus), septohippocampal nucleus, medial septal nucleus, nucleus of the diagonal band, principal nucleus, interfascicular nucleus, transverse nucleus , amygdala, hypothalamus (periventricular zone, paraventricular nucleus, posterior magnocellular part), premammillary nucleus.
Brainstem: parabrachial nucleus, nucleus of the solitary tract, ventrolateral medulla.
Cerebellum: Purkinje cell layers.
Species:  Rat
Technique:  in situ hybridisation.
References:  129
Kidney: preglomerular arterioles.
Species:  Rat
Technique:  RT-PCR.
References:  92
Human eosinophils.
Species:  None
Technique:  Immunohistochemistry, Western blotting, flow cytometry.
References:  64
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of cAMP levels in HEK 293 cells transfected with the human EP4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Stimulation of cAMP accumulation.
References:  118
Measurement of cAMP levels in Xenopus oocytes transfected with the human EP4 receptor and the cystic fibrosis transmembrane conductance regulator (a cAMP-activated Cl- channel).
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of cAMP accumulation.
References:  8,37
Measurement of T-cell factor (Tcf)/lymphoid enhancer factor (Lef) signalling in HEK 293 cells transfected with the human EP4 receptor using a Tcf/Lef-responsive luciferase reporter gene. In addition, measurement of the phosphorylation of glycogen synthase kinase-3 (GSK-3) and Akt kinase.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Activation of Tcf/Lef signalling via a PI3K-dependent pathway, phosphorylation of GSK-3 and Akt kinase.
References:  34
Measurement of ERK phosphorylation and expression of early growth response factor-1 (EGR-1) in HEK 293 cells transfected with the human EP4 receptor.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Activation of ERK signalling via a PI3K-dependent pathway and stimulation of EGR-1 expression.
References:  35
Measurement of cAMP and apoptosis in RP-1 periosteal cells endogenously expressing the EP4 receptor.
Species:  Rat
Tissue:  RP-1 periosteal cell line.
Response measured:  Stimulation of cAMP accumulation and suppression of apoptosis.
References:  65
Measurement of cAMP levels and mucin secretion in human LS174T cells endogenously expressing the EP4 receptor.
Species:  Human
Tissue:  Colonic epithelial cell line LS174T.
Response measured:  Stimulation of cAMP accumulation and mucin exocytosis.
References:  10
Measurement of cAMP levels in rat neutrophils endogenously expressing the EP4 receptor. In addition, measurement of FMLP-stimulated neutrophil aggregation following EP4 activation.
Species:  Rat
Tissue:  Neutrophils.
Response measured:  Stimulation of cAMP accumulation and inhibition of FMLP-stimulated neutrophil aggregation.
References:  119
Measurement of cAMP levels in COS-7 cells transfected with the human EP4 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Stimulation of cAMP accumulation.
References:  5
Physiological Functions
Initiation of immune responses.
Species:  Mouse
Tissue:  In vivo.
References:  50
Renal vasodilation.
Species:  Rat
Tissue:  In vivo (renal artery).
References:  92
Promotion of sleep.
Species:  Rat
Tissue:  In vivo.
References:  126
Stimulation of cell differentiation (simultaneously with EP2).
Species:  Rat
Tissue:  Primary chondrocytes.
References:  70
Reduction in osteoclast motility.
Species:  Rat
Tissue:  Osteoclasts.
References:  87
Follicle growth, IL-8 expression and neutrophil infiltration.
Species:  Rat
Tissue:  In vivo (ovary).
References:  25
Stimulation of gastric acid secretion.
Species:  Rat
Tissue:  In vivo (stomach).
References:  53
Intestinal protection.
Species:  Rat
Tissue:  In vivo (intestine).
References:  57-58
Role in the neonatal adaptation of the circulatory system.
Species:  Mouse
Tissue:  In vivo.
References:  104
Inhibition of TNFα formation.
Species:  Mouse
Tissue:  Kupffer cells.
References:  29
Role in intestinal homeostasis by keeping mucosal integrity and downregulating immune response.
Species:  Mouse
Tissue:  In vivo.
References:  49
Maintenance of bone mass and fracture healing.
Species:  Mouse
Tissue:  In vivo.
References:  62
Stimulation of renin secretion and enhanced salt and water excretion.
Species:  Mouse
Tissue:  In vivo.
References:  86
Duodenal HCO3- secretion.
Species:  Mouse
Tissue:  In vivo (duodenum).
References:  110
Bone production.
Species:  Rat
Tissue:  In vivo (trabecular bone).
References:  65
Blood pressure regulation (female only).
Species:  Mouse
Tissue:  In vivo.
References:  7
Stimulation of renin release and renal vasodilation.
Species:  Mouse
Tissue:  In vivo.
References:  103
Selective suppression of EP4 receptor signalling may have therapeutic value in rheumatoid arthritis both by modifying inflammatory arthritis and by relieving pain.
Species:  Mouse
Tissue:  Knee and ankle joints.
References:  18
EP4 agonist inhibited LPS-induced mucus secretion from airway epithelial cells.
Species:  Human
Tissue:  Nasal epithelial cells.
References:  39
EP4 receptors mediate vasorelaxation.
Species:  Human
Tissue:  Pulmonary vein, saphenous veins, cerebral artery, uterine artery.
References:  9,21,31-32
PGE2 and EP4 agonists induced potent relaxations of human airways via EP4 receptor.
Species:  Human
Tissue:  Bronchial preparation.
References:  11,16
Endothelial cell migration and angiogenesis in vivo are produced by EP4 receptor activation.
Species:  Human
Tissue:  Human prostate cancer cell lines.
References:  45
Inhibition of platelet aggregation.
Species:  Human
Tissue:  Whole blood.
References:  44,90
Protective effect of EP4 receptor against allergic responses by inhibiting the interaction of eosinophils with the endothelium.
Species:  Human
Tissue:  Human peripheral blood eosinophils.
References:  56,64
Inhibition of B lymphocyte cell proliferation.
Species:  Human
Tissue:  B lymphocyte cells.
References:  75
The prostaglandin E2 type 4 receptor participates in the response to acute oxidant stress in airway epithelial cells.
Species:  Human
Tissue:  Calu-3 cell line.
References:  47
EP4 receptor inhibition attenuated aneurysm formation by lowering MMP activity and cytokine release.
Species:  Human
Tissue:  Aortic aneurysmal tissue and cells.
References:  122
Prostaglandin E2 regulates the expression of connective tissue growth factor and MMPs in human osteoarthritic chondrocytes via the EP4 receptor.
Species:  Human
Tissue:  Articular cartilage.
References:  6,66,84
Endogenous PGE2 produced in rheumatoid synovium negatively regulates aberrant synovial overgrowth and the development of osteoclast activity via EP4 receptror.
Species:  Human
Tissue:  Synovial tissue.
References:  69,105
Ductus arteriosus closure, involvement of EP4 receptor.
Species:  Human
Tissue:  Ductus arteriosus.
References:  83,104,124
PGE2-receptor subtype EP4-dependent adherence of mastocytoma P-815 cells to matrix components.
Species:  Mouse
Tissue:  P-815 mastocytoma cells.
References:  52
Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of abdominal aorta aneurysm in the angiotensin II mouse model.
Species:  Mouse
Tissue:  Aorta.
References:  17
EP4 receptor-mediated vasorelaxation is endothelium-dependent and involved endothelial nitric-oxide synthase and cGMP.
Species:  Rat
Tissue:  Aorta.
References:  43
EP4 receptor mediates the dilatory effect of PGE2 in the craniovascular system.
Species:  Rat
Tissue:  Cranial arteries.
References:  77
Selective EP4 agonist inactivates T-cells, which in turn moderates the progression of experimental rat autoimmune myocarditis.
Species:  Rat
Tissue:  T-cells.
References:  82
EP4 receptor agonist inhibited mucus secretion from airway epithelial cells.
Species:  Rat
Tissue:  Nasal epithelial cells.
References:  39-40
The activation of EP4 receptor suppresses the release of cytokines and chemokines from macrophages and T-cells
Species:  Human
Tissue:  Macrophage cells.
References:  111
Cardiac myocyte EP4 receptor plays a role in hypertrophy via activation of Stat-3.
Species:  Mouse
Tissue:  Cardiomyocytes.
References:  94
Human lung carcinoma cell growth is dependent of EP4 signaling.
Species:  Human
Tissue:  Lung carcinoma cells.
References:  130
EP4 receptor agonist reduces MMP-2 and -9 activities and improves cardiac function in a rat model of ischemia-reperfusion injury.
Species:  Rat
Tissue:  Heart.
References:  41
Physiological Consequences of Altering Gene Expression
EP4 receptor knockout mice exhibit weak bones.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3
EP4 receptor knockout mice exhibit impaired intestinal homeostasis.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  49
EP4 receptor knockout mice exhibit reduced PGE2-induced vasodepression compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  7
EP4 receptor knockout mice do not exhibit LPS-induced bone resorption, as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  99
Bone marrow macrophages from EP4 knockout mice do not exhibit PGE2-induced inhibition of cytokine release, as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  80
Kupffer cells from EP4 receptor knockout mice do not exhibit the inhibition of TNFα formation, as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  29
Approximately 95% of neonatal EP4 receptor knockout mice become pale and lethargic around 24 hours after birth and die within 72 hours following birth. The dead neonates exhibit an open ductus arteriosus, whilst the surviving knockout mice exhibit a partially closed ductus arteriosus. These phenotypes are associated with Ptger4tm1Matb/Ptger4tm1Matb (involves: 129S6/SvEvTac * C57BL/6) and Ptger4tm1Aic/Ptger4tm1Aic (involves: 129P2/OlaHsd * C57BL/6) knockouts.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  50,71,102,104,124
EP4 receptor knockout mice exhibit impaired migration of Langerhans cells to draining lymph nodes.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  50
Cocultures of mouse mammary cancer cell lines and bone marrow cells from EP4 receptor knockout mice exhibit abolished osteoclast formation.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  88
EP4 receptor knockout mice exhibit a decrease in bone mass and impaired fracture healing.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  62
EP4 receptor knockout mice exhibit reductions in furosemide-stimulated enhancement of diuresis and electrolyte excretion and plasma renin concentration.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  86
EP4 receptor knockout mice exhibit inhibition of the disruption of the blood-aqueous barrier and leukocyte infiltration in the eye, as seen in the wild-type.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  12
Prostanglandin E2-induced bone formation is impaired in EP4 knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  125
In kidney from EP4(-/-) mice, tubulointerstitial fibrosis was significantly augmented compared with that in wild-type kidneys after unilateral ureteral obstruction.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  78
PGE2 mediated salt and water excretion via EP4 receptor.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  86,93
Renin stimulation in EP4(-/-) mice was significantly reduced by ∼70% compared with wild-type controls.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  27
EP4 is involved in the maintenance of auditory function.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  38
Protective role of neuronal EP4 signaling in cerebral ischemia.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  63
In advanced atherosclerosis, EP4 deficiency did not alter atherosclerotic lesion size, but yielded plaques with exacerbated inflammation and altered lesion composition.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  112
Deficiency of EP4 receptor regulates (boosted or attenuated) inflammation and abdominal aortic aneurysm formation induced by angiotensin II in hypercholesterolemic mice.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  113,122
Ptger4tm1Bhk/Ptger4tm1Bhk (involves: 129P2/OlaHsd * 129S/SvEv) knockout mice display abnormal capillary morphology, abnormal lung morphology, abnormal pulmonary circulation, decreased pulmonary vascular resistance, hepatic steatosis, increased lung weight, liver vascular congestion, lung hemorrhage, lung vascular congestion, lymphangiectasis, patent ductus arteriosus and pulmonary edema.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  83
Ptger4tm1Aic/Ptger4tm1Aic (involves: 129P2/OlaHsd * C57BL/6Cr) knockout mice display preneoplasia and decreased incidence of chemically-induced tumors.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  76
Ptger4tm1Bhk/Ptger4tm1Bhk (involves: 129P2/OlaHsd * C57BL/6 * DBA/2) knockout mice display decreased susceptibility to induced arthritis, rheumatoid arthritis, abnormal prostaglandin level, abnormal cytokine level (for example interleukin-6), abnormal macrophage physiology, abnormal circulating serum amyloid protein level and abnormal vascular regression.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  68,97
Calvarial cultures and long bone cultures from EP4 receptor knockout mice exhibit abnormal calcium ion homeostasis in the form of abolished calcium release in response to PGE2, compared to wild-type mice. This phenotpe is observed in Ptger4tm1.2Matb/Ptger4tm1.2Matb (B6.129S6-Ptger4tm1.2Matb) and Ptger4tm1.2Matb/Ptger4+ (B6.129S6-Ptger4tm1.2Matb) knockouts.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  128
Physiological Consequences of Altering Gene Expression Comments
Deletion of this single gene has been reported to create a mouse model of patent ductus arteriosus, a congenital heart disorder where the ductus arteriosus fails to close spontaneously in neonates (see OMIM:607411) [83].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ptger4tm1.2Matb Ptger4tm1.2Matb/Ptger4tm1.2Matb
B6.129S6-Ptger4
MGI:104311  MP:0004231 abnormal calcium ion homeostasis PMID: 16303601 
Ptger4+|Ptger4tm1.2Matb Ptger4tm1.2Matb/Ptger4+
B6.129S6-Ptger4
MGI:104311  MP:0004231 abnormal calcium ion homeostasis PMID: 16303601 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0003658 abnormal capillary morphology PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0008595 abnormal circulating interleukin-6 level PMID: 12208866 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0010214 abnormal circulating serum amyloid protein level PMID: 12208866 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0008713 abnormal cytokine level PMID: 12208866 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0005362 abnormal Langerhans cell physiology PMID: 12740571 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0001175 abnormal lung morphology PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0002451 abnormal macrophage physiology PMID: 12208866 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0008396 abnormal osteoclast differentiation PMID: 10749873 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0001541 abnormal osteoclast physiology PMID: 10749873 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0009811 abnormal prostaglandin level PMID: 12208866 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0002295 abnormal pulmonary circulation PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0002270 abnormal respiratory alveoli morphology PMID: 9600059 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0001828 abnormal T cell activation PMID: 12740571 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0000364 abnormal vascular regression PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0006138 congestive heart failure PMID: 9600059 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6Cr
MGI:104311  MP:0004502 decreased incidence of chemically-induced tumors PMID: 11782353 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0008567 decreased interferon-gamma secretion PMID: 12740571 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0003035 decreased pulmonary vascular resistance PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0008770 decreased survivor rate PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0003436 decreased susceptibility to induced arthritis PMID: 12208866 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0005616 decreased susceptibility to type IV hypersensitivity reaction PMID: 12740571 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0005095 decreased T cell proliferation PMID: 12740571 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0002753 dilated heart left ventricle PMID: 9600059 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0010557 dilated pulmonary artery PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0002628 hepatic steatosis PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0005630 increased lung weight PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0005202 lethargy PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0010019 liver vascular congestion PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0001182 lung hemorrhage PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0010018 lung vascular congestion PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0010018 lung vascular congestion PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0004038 lymphangiectasis PMID: 9363893 
Ptger4tm1Matb Ptger4tm1Matb/Ptger4tm1Matb
involves: 129S6/SvEvTac * C57BL/6
MGI:104311  MP:0002058 neonatal lethality PMID: 15354288 
Ptger4tm1.1Matb Ptger4tm1.1Matb/Ptger4tm1.1Matb
involves: 129S6/SvEvTac * C57BL/6
MGI:104311  MP:0002169 no abnormal phenotype detected PMID: 15354288 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0003717 pallor PMID: 9600059 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0003139 patent ductus arteriosus PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0003139 patent ductus arteriosus PMID: 9363893 
Ptger4tm1Matb Ptger4tm1Matb/Ptger4tm1Matb
involves: 129S6/SvEvTac * C57BL/6
MGI:104311  MP:0003139 patent ductus arteriosus PMID: 15354288 
Ptger4tm1.2Matb Ptger4tm1.2Matb/Ptger4tm1.2Matb
involves: 129S6/SvEvTac * C57BL/6
MGI:104311  MP:0003139 patent ductus arteriosus PMID: 15354288 
Ptger4tm1.2Matb Ptger4tm1.2Matb/Ptger4tm1.2Matb
involves: 129S6/SvEvTac * C57BL/6
MGI:104311  MP:0002081 perinatal lethality PMID: 15354288 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6
MGI:104311  MP:0002082 postnatal lethality PMID: 9600059 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0002082 postnatal lethality PMID: 9363893 
Ptger4tm1Aic Ptger4tm1Aic/Ptger4tm1Aic
involves: 129P2/OlaHsd * C57BL/6Cr
MGI:104311  MP:0002009 preneoplasia PMID: 11782353 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * 129S/SvEv
MGI:104311  MP:0003828 pulmonary edema PMID: 9363893 
Ptger4tm1Bhk Ptger4tm1Bhk/Ptger4tm1Bhk
involves: 129P2/OlaHsd * C57BL/6 * DBA/2
MGI:104311  MP:0003561 rheumatoid arthritis PMID: 12208866 
Biologically Significant Variants
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  In patients with aspirin-intolerant chronic urticaria (AICU), the PTGER4-1254 G allele demonstrated a higher frequency and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.
SNP accession: 
References:  89
Type:  Single nucleotide polymorphisms
Species:  Human
Description:  Variations in the prostaglandin EP4 receptor gene (PTGER4) are associated with primary graft dysfunction.
References:  22
General Comments
The recombinant EP4 receptor was originally identified as EP2 [8,42].

The EP2 and EP4 receptors are thought to mediate most of the hemodynamic responses to PGE2 in the female but not the male mouse [7].

References

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