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EP4 receptor

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 343

Nomenclature: EP4 receptor

Family: Prostanoid receptors

Contents:

Gene and Protein Information Click here for help
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 6,12
Mouse 7 513 15 1.99 cM Ptger4 prostaglandin E receptor 4 (subtype EP4) 48
Rat 7 488 2q16 Ptger4 prostaglandin E receptor 4 18,116
Previous and Unofficial Names Click here for help
EP2 [6,12,43,48,116] | PGE receptor EP4 subtype | prostanoid EP4 receptor
Database Links Click here for help
Specialist databases
GPCRdb pe2r4_human (Hs), pe2r4_mouse (Mm), pe2r4_rat (Rn)
Other databases
Alphafold P35408 (Hs), P32240 (Mm), P43114 (Rn)
ChEMBL Target CHEMBL1836 (Hs), CHEMBL2489 (Mm), CHEMBL4086 (Rn)
DrugBank Target P35408 (Hs)
Ensembl Gene ENSG00000171522 (Hs), ENSMUSG00000039942 (Mm), ENSRNOG00000013240 (Rn)
Entrez Gene 5734 (Hs), 19219 (Mm), 84023 (Rn)
Human Protein Atlas ENSG00000171522 (Hs)
KEGG Gene hsa:5734 (Hs), mmu:19219 (Mm), rno:84023 (Rn)
OMIM 601586 (Hs)
Pharos P35408 (Hs)
RefSeq Nucleotide NM_000958 (Hs), NM_008965 (Mm), NM_032076 (Rn)
RefSeq Protein NP_000949 (Hs), NP_032991 (Mm), NP_114465 (Rn)
UniProtKB P35408 (Hs), P32240 (Mm), P43114 (Rn)
Wikipedia PTGER4 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human prostaglandin E receptor EP4 in complex with Fab and ONO-AE3-208
PDB Id:  5YWY
Ligand:  ONO-AE3-208
Resolution:  3.2Å
Species:  Human
References:  131
Image of receptor 3D structure from RCSB PDB
Description:  Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein
PDB Id:  7D7M
Resolution:  3.3Å
Species:  Human
References:  99
Natural/Endogenous Ligands Click here for help
PGD2
PGE1
PGE2
PGF2α
PGI2
Comments: PGE2 is the principal endogenous agonist
Potency order of endogenous ligands
PGE2 = PGE1 > PGF2α, PGI2 > PGD2, thromboxane A2

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]PGE2 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Rn Full agonist 9.0 pKd 18
⤷ pKd 9.0 [18]
PGE2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Mm Full agonist 8.6 pKd 62
⤷ pKd 8.6 (Kd 2.5x10-9 M) [62]
[3H]PGE2 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist 7.6 – 9.5 pKd 1,26,134-135
⤷ pKd 7.6 – 9.5 (Kd 2.4x10-8 – 3x10-10 M) [1,26,134-135]
KMN-159 Small molecule or natural product Rn Agonist 9.6 pKi 103
⤷ pKi 9.6 (Ki 2.4x10-10 M) [103]
Description: Binding Ki for rat EP4 receptor
L902688 Small molecule or natural product Hs Agonist 9.4 pKi 148
⤷ pKi 9.4 (Ki 3.8x10-10 M) [148]
KMN-159 Small molecule or natural product Hs Agonist 9.4 pKi 11
⤷ pKi 9.4 (Ki 3.8x10-10 M) [11]
PGF2α Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 9.1 – 9.5 pKi 1,26,123
⤷ pKi 9.1 – 9.5 (Ki 8x10-10 – 3.2x10-10 M) [1,26,123]
PGE1 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 9.2 pKi 18
⤷ pKi 9.2 [18]
rivenprost Small molecule or natural product Click here for species-specific activity table Mm Full agonist 9.2 pKi 146
⤷ pKi 9.2 [146]
ONO-AE1-437 Small molecule or natural product Mm Agonist 9.1 pKi 83
⤷ pKi 9.1 (Ki 7.1x10-10 M) [83]
PGE2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 9.0 pKi 18
⤷ pKi 9.0 [18]
11-deoxy-PGE2 Small molecule or natural product Rn Full agonist 9.0 pKi 18
⤷ pKi 9.0 [18]
TCS 2510 Small molecule or natural product Hs Agonist 8.9 pKi 148
⤷ pKi 8.9 (Ki 1.2x10-9 M) [148]
11-deoxy-PGE1 Small molecule or natural product Hs Full agonist 8.9 pKi 26
⤷ pKi 8.9 [26]
PGD2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 8.7 – 9.0 pKi 26,123
⤷ pKi 8.7 – 9.0 (Ki 2x10-9 – 1x10-9 M) [26,123]
PGE1 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 8.8 pKi 26
⤷ pKi 8.8 (Ki 1.58x10-9 M) [26]
PGE1 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Mm Full agonist 8.7 pKi 62
⤷ pKi 8.7 [62]
PGE2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Mm Full agonist 8.5 – 8.7 pKi 62,124
⤷ pKi 8.5 – 8.7 (Ki 3x10-9 – 2x10-9 M) [62,124]
PGE2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 8.1 – 9.1 pKi 1,26,92,123,135
⤷ pKi 8.1 – 9.1 (Ki 7.94x10-9 – 7.94x10-10 M) [1,26,92,123,135]
13,14-dihydro-PGE1 Small molecule or natural product Hs Full agonist 8.5 pKi 26
⤷ pKi 8.5 [26]
L-161,982 (EP4A) Small molecule or natural product Immunopharmacology Ligand Hs Agonist 7.6 – 8.5 pKi 76,148
⤷ pKi 7.6 – 8.5 [76,148]
ONO-AE1-329 Small molecule or natural product Click here for species-specific activity table Mm Full agonist 8.0 pKi 124
⤷ pKi 8.0 (Ki 1x10-8 M) [124]
MB-28767 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.5 – 8.0 pKi 1,123
⤷ pKi 7.5 – 8.0 [1,123]
MB-28767 Small molecule or natural product Click here for species-specific activity table Rn Full agonist 7.6 pKi 18
⤷ pKi 7.6 [18]
11-deoxy-PGE1 Small molecule or natural product Click here for species-specific activity table Mm Full agonist 7.6 pKi 62
⤷ pKi 7.6 [62]
misoprostol (free acid form) Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.6 pKi 1
⤷ pKi 7.6 [1]
19(R)-OH-PGE2 Small molecule or natural product Click here for species-specific activity table Rn Full agonist 7.5 pKi 18
⤷ pKi 7.5 [18]
L-161,982 (EP4A) Small molecule or natural product Immunopharmacology Ligand Rn Agonist 7.5 pKi 76
⤷ pKi 7.5 [76]
cicaprost Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Full agonist 7.4 pKi 1
⤷ pKi 7.4 [1]
enprostil Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.4 pKi 26
⤷ pKi 7.4 [26]
16,16-dimethyl-PGE2 Small molecule or natural product Click here for species-specific activity table Mm Full agonist 7.4 pKi 62
⤷ pKi 7.4 [62]
1-OH-PGE1 Small molecule or natural product Mm Full agonist 6.7 pKi 62
⤷ pKi 6.7 [62]
carbacyclin Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.5 pKi 1
⤷ pKi 6.5 [1]
MB-28767 Small molecule or natural product Click here for species-specific activity table Mm Full agonist 6.3 pKi 62
⤷ pKi 6.3 (Ki 5x10-7 M) [62]
PGF2α Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 6.2 pKi 18
⤷ pKi 6.2 [18]
treprostinil Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 6.1 pKi 134
⤷ pKi 6.1 (Ki 8x10-7 M) [134]
PGD2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 5.9 pKi 18
⤷ pKi 5.9 [18]
U46619 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 5.7 pKi 1
⤷ pKi 5.7 [1]
iloprost Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Full agonist 4.6 – 6.7 pKi 1,26,134
⤷ pKi 4.6 – 6.7 (Ki 2.3x10-5 – 2.1x10-7 M) [1,26,134]
U46619 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Rn Full agonist 5.6 pKi 18
⤷ pKi 5.6 [18]
carbacyclin Small molecule or natural product Click here for species-specific activity table Mm Full agonist 5.6 pKi 62
⤷ pKi 5.6 [62]
iloprost Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Mm Full agonist 5.6 pKi 62
⤷ pKi 5.6 [62]
MRE-269 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 5.3 pKi 67
⤷ pKi 5.3 (Ki 4.9x10-6 M) [67]
misoprostol (methyl ester) Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 5.3 pKi 1
⤷ pKi 5.3 [1]
beraprost Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.1 pKi 67
⤷ pKi 5.1 (Ki 7.2x10-6 M) [67]
PGI2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 5.1 pKi 26
⤷ pKi 5.1 [26]
butaprost (free acid form) Small molecule or natural product Click here for species-specific activity table Rn Full agonist 4.8 pKi 18
⤷ pKi 4.8 [18]
butaprost (free acid form) Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.7 pKi 1
⤷ pKi 4.7 [1]
PGE1 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 9.5 pEC50 68
⤷ pEC50 9.5 (EC50 3.1x10-10 M) [68]
11-deoxy-PGE1 Small molecule or natural product Hs Agonist 9.3 pEC50 68
⤷ pEC50 9.3 (EC50 4.7x10-10 M) [68]
L902688 Small molecule or natural product Hs Agonist 8.1 – 10.3 pEC50 37,68
⤷ pEC50 8.1 – 10.3 (EC50 9x10-9 – 5x10-11 M) [37,68]
CP734432 Small molecule or natural product Hs Agonist 9.0 pEC50 106
⤷ pEC50 9.0 (EC50 1x10-9 M) [106]
PGD2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 8.8 pEC50 68
⤷ pEC50 8.8 (EC50 1.7x10-9 M) [68]
MB-28767 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.8 pEC50 68
⤷ pEC50 7.8 (EC50 1.77x10-8 M) [68]
ONO-AE1-329 Small molecule or natural product Hs Full agonist 7.7 – 7.8 pEC50 36-37
⤷ pEC50 7.7 – 7.8 (EC50 2.2x10-8 – 1.6x10-8 M) [36-37]
treprostinil Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 6.7 pEC50 134
⤷ pEC50 6.7 (EC50 2x10-7 M) [134]
iloprost Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Full agonist 6.4 pEC50 134
⤷ pEC50 6.4 (EC50 4x10-7 M) [134]
PGE2 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 6.1 pEC50 68
⤷ pEC50 6.1 (EC50 9x10-7 M) [68]
PGF2α Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Immunopharmacology Ligand Hs Full agonist 6.1 pEC50 68
⤷ pEC50 6.1 (EC50 9x10-7 M) [68]
CP734432 Small molecule or natural product Hs Full agonist 8.7 pIC50 106
⤷ pIC50 8.7 (IC50 2x10-9 M) [106]
17-phenyl-ω-trinor-PGE2 Small molecule or natural product Click here for species-specific activity table Hs Agonist - - 130
⤷ [130]
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 [59].
ONO-4232, a selective EP4 agonist is in Phase I clinical trials in acute heart failure [133].
A conjugate of an EP4a agonist that reverses osteopenia in a rat model [74] should not be confused with the L-161,982 (EP4A) antagonist in the table below. Chemistry of EP4 agonist conjugates in disclosed in Arns et al. (2012) [7].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
TG6-129 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 5.4 pKB 41
⤷ pKB 5.4 (KB 3.9x10-6 M) [41]
TG11-77 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 5.3 pKB 5
⤷ pKB 5.3 (KB 5.3x10-6 M) [5]
CR6086 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 9.3 pKd 22
⤷ pKd 9.3 (Kd 5.4x10-10 M) [22]
CR6086 Small molecule or natural product Immunopharmacology Ligand Rn Antagonist 8.7 pKd 22
⤷ pKd 8.7 (Kd 1.96x10-9 M) [22]
CR6086 Small molecule or natural product Immunopharmacology Ligand Mm Antagonist 8.7 pKd 22
⤷ pKd 8.7 (Kd 2.14x10-9 M) [22]
ER819762 Small molecule or natural product Hs Antagonist 9.3 pKi 17
⤷ pKi 9.3 (Ki 5.6x10-10 M) [17]
MK-2894 Small molecule or natural product Hs Antagonist 9.3 pKi 1,17,25
⤷ pKi 9.3 (Ki 5.6x10-10 M) [1,17,25]
MF 498 Small molecule or natural product Hs Antagonist 9.1 pKi 25
⤷ pKi 9.1 (Ki 7x10-10 M) [25]
ONO-AE3-208 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Antagonist 8.9 pKi 57
⤷ pKi 8.9 [57]
evatanepag Small molecule or natural product Ligand has a PDB structure Hs Antagonist 8.6 pKi 87
⤷ pKi 8.6 (Ki 2.51x10-9 M) [87]
ONO-AE2-227 Small molecule or natural product Click here for species-specific activity table Mm Antagonist 8.6 pKi 89
⤷ pKi 8.6 (Ki 2.7x10-9 M) [89]
CJ-042794 Small molecule or natural product Hs Antagonist 8.5 pKi 86
⤷ pKi 8.5 (Ki 3.1x10-9 M) [86]
BGC201531 Small molecule or natural product Hs Antagonist 7.9 pKi 80
⤷ pKi 7.9 (Ki 1.26x10-8 M) [80]
grapiprant Small molecule or natural product Primary target of this compound Hs Antagonist 7.9 pKi 92
⤷ pKi 7.9 (Ki 1.3x10-8 M) [92]
CR6086 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 7.8 pKi 22
⤷ pKi 7.8 (Ki 1.66x10-8 M) [22]
ONO-AE3-240 Small molecule or natural product Click here for species-specific activity table Mm Antagonist 7.2 pKi 4
⤷ pKi 7.2 (Ki 5.8x10-8 M) [4]
GW 627368 Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 7.0 – 7.1 pKi 135-136
⤷ pKi 7.0 – 7.1 (Ki 1x10-7 – 7.94x10-8 M) [135-136]
AH23848 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 4.9 – 5.6 pKi 1,26
⤷ pKi 4.9 – 5.6 [1,26]
pKi 5.0 [1]
AH23848 Small molecule or natural product Rn Antagonist 5.1 pKi 18
⤷ pKi 5.1 [18]
AH23848 (racemic) Small molecule or natural product Rn Antagonist 5.0 pKi 18
⤷ pKi 5.0 [18]
compound 47 [PMID: 35640059] Small molecule or natural product Hs Antagonist 8.3 pIC50 132
⤷ pIC50 8.3 (IC50 5x10-9 M) [132]
Description: Measuring antagonism of PGE2-mediated calcium flux in HEK293 cells transiently expressing hEP4, using Promega's proprietary GloSensor cAMP assay system
BAY1316957 Small molecule or natural product Hs Antagonist 7.8 pIC50 10
⤷ pIC50 7.8 (IC50 1.53x10-8 M) [10]
ER819762 Small molecule or natural product Hs Antagonist 7.2 pIC50 23
⤷ pIC50 7.2 (IC50 7x10-8 M) [23]
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.
The EP4 antagonist grapiprant is approved for the treatment of pain and inflammation in osteoarthritis in dogs [110].
Allosteric Modulators
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
THG213.29 Peptide Rn Negative 5.5 pIC50 69
⤷ pIC50 5.5 (IC50 3x10-6 M) [69]
Immunopharmacology Comments
The EP4 prostanoid receptor is one of four receptor subtypes for prostaglandin PGE2. The anti- and pro-inflammatory (and non-inflammatory) activities of this receptor are reviewed in [144]. Foudi et al. (2012) [35] review the presence and role of EP1-4 receptors in human inflammation and immune cells. The PGE2/EP4 receptor axis appears to act as an amplifier of cytokine (like IL-6) activity and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. Results from several mouse models indicate that the PGE2/EP4 receptor axis is important in regulating the inflammatory response across a range of tissues [29,31,112,122,142]. PGE2, acting via EP2 and EP4 receptors in synovial tissue appears to contribute to the progression of rheumatoid arthritis (RA) in a rat model [139]. Blocking EP4 and EP2 using their antagonists or genetically modified animals prevents inflammation in CNS, gut and skin in animal models for multiple sclerosis, colitis, psoriasis, atopic dermatitis and contact hypersensitivity [31,70,77,112,140]. EP4 antagonists with anti-inflammatory action are discussed in [56]. CR6086 is an example of a EP4 antagonist that is in clinical development for RA.

The EP4 receptor is discussed in this review of immuno-oncology [2].The roles of PGE2 in chronic immune-mediated inflammation is reviewed here [141].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  94
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Other - See Comments
Comments:  A second EP4 signaling pathway is PI3K dependent via G protein Gi activation.
References:  38,40,111,114
Tissue Distribution Click here for help
Abdominal aorta aneurysm.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR, Western blotting.
References:  143
Mouth: gingival fibroblasts.
Species:  Human
Technique:  RT-PCR.
References:  98
Eye: corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, conjunctival and iridal stroma cells.
Species:  Human
Technique:  Immunohistochemistry.
References:  117
Kidney: glomeruli, media of arteries.
Species:  Human
Technique:  Immunohistochemistry, Western blotting.
References:  85
Pulmonary veins.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR.
References:  37
Cultured mastocyte.
Species:  Human
Technique:  RT-PCR.
References:  33
Penis: corpus cavernosum.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  63
Carotid atherosclerotic plaques.
Species:  Human
Technique:  Immunohistochemistry, RT-PCR, Western blotting.
References:  24,125
Small intestine > lung, kidney, thymus, uterus, brain.
Species:  Human
Technique:  Northern blotting.
References:  12
Kidney: glomerulus.
Species:  Human
Technique:  in situ hybridization.
References:  19
Gastrointestinal tract: small intestine and colon (intestinal mucosal layer), stomach (gastric mucosal layer containing epithelial cells).
Species:  Rat
Technique:  Northern blotting.
References:  28
Kidney: outer medulla, papilla > cortex.
Species:  Rat
Technique:  RNase protection assay.
References:  54
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:  150
Kidney: preglomerular arterioles.
Species:  Rat
Technique:  RT-PCR.
References:  107
Human eosinophils.
Species:  None
Technique:  Immunohistochemistry, Western blotting, flow cytometry.
References:  75
Expression Datasets Click here for help

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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 Click here for help
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:  137
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:  12,43
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:  39
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:  40
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:  76
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:  14
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:  138
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:  6
Physiological Functions Click here for help
Renal vasodilation.
Species:  Rat
Tissue:  In vivo (renal artery).
References:  107
Promotion of sleep.
Species:  Rat
Tissue:  In vivo.
References:  147
Stimulation of cell differentiation (simultaneously with EP2).
Species:  Rat
Tissue:  Primary chondrocytes.
References:  83
Reduction in osteoclast motility.
Species:  Rat
Tissue:  Osteoclasts.
References:  101
Follicle growth, IL-8 expression and neutrophil infiltration.
Species:  Rat
Tissue:  In vivo (ovary).
References:  30
Stimulation of gastric acid secretion.
Species:  Rat
Tissue:  In vivo (stomach).
References:  61
Intestinal protection.
Species:  Rat
Tissue:  In vivo (intestine).
References:  65-66
Role in the neonatal adaptation of the circulatory system.
Species:  Mouse
Tissue:  In vivo.
References:  120
Inhibition of TNFα formation.
Species:  Mouse
Tissue:  Kupffer cells.
References:  34
Role in intestinal homeostasis by keeping mucosal integrity and downregulating immune response.
Species:  Mouse
Tissue:  In vivo.
References:  57
Initiation of immune responses.
Species:  Mouse
Tissue:  In vivo.
References:  58
Maintenance of bone mass and fracture healing.
Species:  Mouse
Tissue:  In vivo.
References:  71
Stimulation of renin secretion and enhanced salt and water excretion.
Species:  Mouse
Tissue:  In vivo.
References:  100
Duodenal HCO3- secretion.
Species:  Mouse
Tissue:  In vivo (duodenum).
References:  126
Bone production.
Species:  Rat
Tissue:  In vivo (trabecular bone).
References:  76
Blood pressure regulation (female only).
Species:  Mouse
Tissue:  In vivo.
References:  9
Stimulation of renin release and renal vasodilation.
Species:  Mouse
Tissue:  In vivo.
References:  119
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:  23
EP4 agonist inhibited LPS-induced mucus secretion from airway epithelial cells.
Species:  Human
Tissue:  Nasal epithelial cells.
References:  45
EP4 receptors mediate vasorelaxation.
Species:  Human
Tissue:  Pulmonary vein, saphenous veins, cerebral artery, uterine artery.
References:  13,26,36-37
PGE2 and EP4 agonists induced potent relaxations of human airways via EP4 receptor.
Species:  Human
Tissue:  Bronchial preparation.
References:  15,20
Endothelial cell migration and angiogenesis in vivo are produced by EP4 receptor activation.
Species:  Human
Tissue:  Human prostate cancer cell lines.
References:  53
Inhibition of platelet aggregation.
Species:  Human
Tissue:  Whole blood.
References:  52,105
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:  64,75
Inhibition of B lymphocyte cell proliferation.
Species:  Human
Tissue:  B lymphocyte cells.
References:  88
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:  55
EP4 receptor inhibition attenuated aneurysm formation by lowering MMP activity and cytokine release.
Species:  Human
Tissue:  Aortic aneurysmal tissue and cells.
References:  143
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:  8,78,97
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:  82,121
Ductus arteriosus closure, involvement of EP4 receptor.
Species:  Human
Tissue:  Ductus arteriosus.
References:  96,120,145
PGE2-receptor subtype EP4-dependent adherence of mastocytoma P-815 cells to matrix components.
Species:  Mouse
Tissue:  P-815 mastocytoma cells.
References:  60
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:  21
EP4 receptor-mediated vasorelaxation is endothelium-dependent and involved endothelial nitric-oxide synthase and cGMP.
Species:  Rat
Tissue:  Aorta.
References:  49
EP4 receptor mediates the dilatory effect of PGE2 in the craniovascular system.
Species:  Rat
Tissue:  Cranial arteries.
References:  90
Selective EP4 agonist inactivates T-cells, which in turn moderates the progression of experimental rat autoimmune myocarditis.
Species:  Rat
Tissue:  T-cells.
References:  95
EP4 receptor agonist inhibited mucus secretion from airway epithelial cells.
Species:  Rat
Tissue:  Nasal epithelial cells.
References:  45-46
The activation of EP4 receptor suppresses the release of cytokines and chemokines from macrophages and T-cells
Species:  Human
Tissue:  Macrophage cells.
References:  127
Cardiac myocyte EP4 receptor plays a role in hypertrophy via activation of Stat-3.
Species:  Mouse
Tissue:  Cardiomyocytes.
References:  109
Human lung carcinoma cell growth is dependent of EP4 signaling.
Species:  Human
Tissue:  Lung carcinoma cells.
References:  151
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:  47
Physiological Consequences of Altering Gene Expression Click here for help
EP4 receptor knockout mice exhibit impaired intestinal homeostasis.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  57
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:  34
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:  9
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:  115
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:  93
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:  58,84,118,120,145
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:  58
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:  102
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:  71
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:  100
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:  16
EP4 receptor knockout mice exhibit weak bones.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3
T cell-specific EP4 deficiency restricts T cell mediated colitis.
Species:  Mouse
Tissue:  Colon
Technique:  Gene targeting in embrionic stem cells
References:  77,140
Prostanglandin E2-induced bone formation is impaired in EP4 knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  146
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:  91
PGE2 mediated salt and water excretion via EP4 receptor.
Species:  Mouse
Tissue: 
Technique:  Targeting in embryonic stem cells..
References:  100,108
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:  32
EP4 is involved in the maintenance of auditory function.
Species:  Mouse
Tissue: