Affinage

PTGER2

Prostaglandin E2 receptor EP2 subtype · UniProt P43116

Length
358 aa
Mass
39.8 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTGER2 (EP2) is a Gs-coupled prostaglandin E2 receptor that signals primarily through adenylyl cyclase–cAMP–PKA to regulate vasodilation, bronchodilation, female fertility, neuroprotection, bone homeostasis, and inflammatory responses across diverse tissues. Cloned from human lung, EP2 binds PGE2 with nanomolar affinity and couples exclusively to Gs to elevate cAMP, activating PKA-dependent downstream effectors including CREB, Tcf/β-catenin, and NF-κB inhibition, thereby driving processes such as amphiregulin-mediated mammary epithelial proliferation, Sclerostin suppression to potentiate Wnt signaling in osteoblasts, MMP-13 repression in chondrocytes, and progesterone synthesis in granulosa cells (PMID:8250933, PMID:15930264, PMID:21436889, PMID:20870807, PMID:17761898). In addition to canonical G-protein signaling, EP2 engages a β-arrestin-dependent, cAMP-independent pathway that suppresses microglial IL-10 production, and myeloid-expressed EP2 drives neuroinflammatory sequelae in stroke and status epilepticus (PMID:25218510, PMID:31036664, PMID:33293358). PTGER2 expression is subject to epigenetic silencing by promoter DNA hypermethylation (augmented by Akt signaling) and direct transcriptional repression by RORC in Th17 cells, the loss of which derepresses EP2 and promotes a pathogenic inflammatory phenotype linked to multiple sclerosis (PMID:20889571, PMID:17533365, PMID:24812667).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Cloning of human EP2 and demonstration of exclusive Gs–cAMP coupling resolved the second-messenger identity of one of the four PGE2 receptor subtypes, distinguishing it from Ca²⁺-coupled receptors.

    Evidence cDNA cloning from human lung, radioligand binding (Kd ~2.2 nM), cAMP and Ca²⁺ measurement in transfected COS-7 cells

    PMID:8250933

    Open questions at the time
    • Downstream effectors beyond cAMP not yet mapped
    • No in vivo functional data
    • Receptor desensitization and trafficking unknown
  2. 1999 High

    Genetic ablation of EP2 established that it is the required receptor for PGE2-mediated arterial vasodilation, salt-sensitive blood pressure homeostasis, and female fertility (ovulation and fertilization), converting pharmacological inference into causal genetic proof.

    Evidence EP2−/− knockout mice with intravenous PGE2 infusion, high-salt diet challenge, and reproductive phenotyping

    PMID:9930871

    Open questions at the time
    • Downstream signaling mediating vasodilation in vivo uncharacterized
    • Whether fertility defect is oocyte- or somatic-cell-autonomous not resolved
    • Renal tubular mechanism of salt handling not defined
  3. 2000 High

    Demonstration that EP2 mediates PGE2-induced bronchodilation expanded its physiological role to airway smooth muscle and explained the paradoxical bronchoconstriction seen when EP2 is absent.

    Evidence EP2−/− mice, barometric plethysmography and mechanical ventilation measurements of airway resistance

    PMID:10846038

    Open questions at the time
    • Airway cell type expressing functional EP2 not identified
    • Contribution of EP2 vs. EP4 in human airways not resolved
  4. 2001 High

    Mapping EP2 to specific renal medullary segments (descending thin limb of Henle, outer medullary vasa recta) with segment-specific cAMP responses provided the anatomical basis for its role in salt and water balance.

    Evidence RNase protection assay, RT-PCR on microdissected nephron segments, cAMP RIA with butaprost in rat kidney

    PMID:11352840

    Open questions at the time
    • Direct ion-transport targets in these segments not identified
    • Human renal EP2 distribution not confirmed
  5. 2004 High

    EP2 was shown to mediate neuroprotection against excitotoxicity and ischemia via cAMP/PKA, while separately suppressing keratinocyte CCL27 through cAMP-dependent NF-κB inhibition, establishing PKA as a shared effector across cell types.

    Evidence Neuronal cultures with NMDA/OGD ± PKA inhibitors, EP2−/− MCAO stroke model; keratinocyte NF-κB reporter with EP2 agonist and H-89

    PMID:14715958 PMID:15577845

    Open questions at the time
    • Neuroprotective mechanism downstream of PKA (anti-apoptotic targets) unknown
    • Relative contribution of neuronal vs. glial EP2 to neuroprotection not dissected
  6. 2005 High

    Genetic epistasis (MMTV-COX-2 × EP2−/−) demonstrated that EP2 is the obligate receptor coupling COX-2 to mammary hyperplasia, operating through a cAMP/PKA→amphiregulin axis that drives epithelial proliferation.

    Evidence Bigenic mouse model, EP2 agonist treatment of tumor cells, PKA inhibitor, amphiregulin RT-PCR, cAMP assay

    PMID:15930264

    Open questions at the time
    • Whether amphiregulin acts through EGFR in this context not directly shown
    • Contribution to malignant progression beyond hyperplasia not addressed
  7. 2007 High

    Multiple studies established EP2 as a transcriptional amplifier of its own ligand supply (COX-2 → PGE2 positive feedback in skin via PKA/CREB), a mediator of progesterone synthesis in granulosa cells, and a cross-talk node with Tcf/β-catenin signaling distinctly through PKA rather than PI3K.

    Evidence EP2 KO and transgenic mice with TPA treatment and CREB phosphorylation; granulosa-lutein cell pharmacology with butaprost/AH6809; Tcf reporter assays with PKA and PI3K inhibitors

    PMID:14607241 PMID:17277233 PMID:17761898

    Open questions at the time
    • CREB target genes downstream of EP2 in skin not cataloged
    • Whether β-catenin activation by EP2 occurs in vivo not confirmed
    • Structural basis for EP2 vs. EP4 pathway selectivity unknown
  8. 2007 High

    Discovery that the PTGER2 promoter is silenced by DNA methylation and repressive histone marks in neuroblastoma revealed that EP2 can function as a growth suppressor when re-expressed, fundamentally altering interpretation of its role in cancer.

    Evidence Bisulfite sequencing, ChIP for histone modifications, PTGER2 transfection rescue with butaprost-induced cAMP, growth inhibition, and apoptosis in neuroblastoma cells

    PMID:17533365

    Open questions at the time
    • Whether EP2 methylation is a driver or passenger event in neuroblastoma not established
    • Generalizability of tumor-suppressive function to other cancer types unclear
  9. 2010 High

    Akt-driven PTGER2 promoter hypermethylation was identified as the mechanism of PGE2 resistance in fibrotic fibroblasts, while EP2 activation was shown to counteract matrix-stiffness-induced fibrogenesis, establishing EP2 silencing as a pathogenic event in pulmonary fibrosis.

    Evidence Bisulfite sequencing, DNMT siRNA, methylation inhibitors in human and mouse fibrotic fibroblasts; EP2 agonist on tunable-stiffness hydrogels

    PMID:20733059 PMID:20889571

    Open questions at the time
    • Whether PTGER2 demethylation reverses established fibrosis in vivo not tested
    • Mechanotransduction pathway linking EP2 to matrix stiffness sensing not defined
  10. 2010 High

    A systematic siRNA screen identified EP2 as the dominant receptor suppressing MMP-13 and other catabolic factors in osteoarthritic chondrocytes via cAMP/PKA, establishing EP2 as a cartilage-protective receptor.

    Evidence siRNA screen of 114 genes, butaprost treatment ± IL-1β, cAMP/PKA inhibitors, MMP-13 ELISA in human OA chondrocytes

    PMID:20870807

    Open questions at the time
    • In vivo validation of EP2-mediated cartilage protection not performed
    • Mechanism of MMP-13 transcriptional repression downstream of PKA not identified
  11. 2011 High

    EP2-mediated suppression of Sclerostin and consequent Wnt/TCF activation in osteoblasts provided a molecular mechanism for the known bone-anabolic effects of PGE2, linking EP2 to the Wnt pathway in bone.

    Evidence EP2 agonist, Ptger2 siRNA, cAMP/PKA inhibitors, Sost/Axin2/Tcf3 RT-PCR in UMR106.01 osteoblastic cells

    PMID:21436889

    Open questions at the time
    • In vivo confirmation of EP2-dependent Sclerostin regulation not shown
    • Whether EP2 acts on osteocytes (the major Sost source) directly not tested
  12. 2012 High

    Epistatic analysis using single and double receptor knockouts demonstrated that EP2 and EP4 cooperate redundantly to protect pancreatic β-cells from STZ-induced destruction, expanding EP2 biology to metabolic homeostasis.

    Evidence PTGER2−/−, PTGER4−/−, double KO mice, EP2/EP4 agonist rescue, blood glucose and insulin measurements

    PMID:22522619

    Open questions at the time
    • Downstream β-cell survival pathway not identified
    • Relevance to autoimmune (type 1) or type 2 diabetes in humans not tested
  13. 2013 High

    EP2 was shown to promote trophoblast adhesion to extracellular matrix via integrin αVβ3 through MEK/MAPK, providing a molecular explanation for how PGE2 facilitates embryo implantation.

    Evidence Butaprost treatment, EP2 antagonist, integrin antibody, MEK inhibitor in porcine and human trophoblast cells

    PMID:23861370

    Open questions at the time
    • Whether EP2 acts on decidual vs. trophoblast side in vivo not resolved
    • Relationship between cAMP-PKA and MEK/MAPK branches in trophoblasts not clarified
  14. 2014 High

    Discovery of β-arrestin-dependent, cAMP-independent EP2 signaling that suppresses microglial IL-10, combined with the finding that RORC directly represses PTGER2 transcription in Th17 cells (with de-repression promoting pathogenic Th17 phenotype in MS), established EP2 as a bidirectional immune regulator whose expression and signaling mode profoundly shape inflammatory outcomes.

    Evidence EP2−/−, β-arrestin-1/2 KO microglia with IL-10 ELISA; ChIP-seq for RORγt at PTGER2 promoter, RORC siRNA, EP2 overexpression in human Th17 cells

    PMID:24812667 PMID:25218510

    Open questions at the time
    • β-arrestin effector complex composition downstream of EP2 not defined
    • Whether RORC-mediated EP2 repression is targetable therapeutically in MS not tested
    • Structural basis for biased signaling through EP2 unknown
  15. 2019 High

    Cell-type-specific conditional knockouts resolved a long-standing paradox: neuronal EP2 promotes ischemic injury (contradicting the earlier congenital KO finding of neuroprotection), while myeloid EP2 drives immune cell infiltration, demonstrating that EP2's net effect in stroke depends on cell-type context and developmental timing of deletion.

    Evidence Inducible (ROSACreER), neuronal (Thy1Cre), and myeloid (Cd11bCre) conditional EP2 KO mice in MCAO stroke model

    PMID:31036664

    Open questions at the time
    • Mechanism by which neuronal EP2 promotes ischemic injury not identified
    • Discrepancy with earlier congenital KO neuroprotection not fully mechanistically explained
  16. 2020 High

    Myeloid EP2 on peripheral (not microglial) CD11b+ cells was identified as the driver of hippocampal IL-6, BBB breakdown, and behavioral impairment after status epilepticus, with systemic EP2 antagonism providing additional neuroprotection beyond what genetic myeloid deletion achieved.

    Evidence CD11b-Cre;EP2lox/lox conditional KO, pilocarpine SE model, IL-6 ELISA, cortical albumin, behavioral scoring, systemic EP2 antagonist

    PMID:33293358

    Open questions at the time
    • Non-myeloid cell types contributing to the additional benefit of systemic EP2 antagonism not identified
    • Downstream signaling from myeloid EP2 to IL-6 induction not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for EP2's biased signaling (Gs-cAMP vs. β-arrestin pathways), the identity of the β-arrestin effector complex, and whether pharmacological biased agonism at EP2 can separate beneficial from detrimental effects in neuroinflammation and cancer remain unresolved.
  • No cryo-EM or crystal structure of EP2 in active state with Gs or β-arrestin
  • β-arrestin signaling effectors downstream of EP2 not identified
  • No biased ligand for EP2 validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474165 Reproduction 3
Partners
ARRB1ARRB2CTNNB1PTGS2RORC

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Human EP2 receptor (PTGER2) was cloned from a lung cDNA library; expressed in COS-7 cells it bound [3H]-PGE2 with Kd ~2.2 nM and coupled exclusively to Gs to increase intracellular cAMP (not Ca2+), establishing its second-messenger mechanism. cDNA cloning, radioligand binding assay, cAMP and Ca2+ measurement in transfected COS-7 cells Biochemical and biophysical research communications High 8250933
1999 Genetic deletion of EP2 (PTGER2) in mice abolished the hypotensive effect of intravenous PGE2 (which instead caused hypertension), demonstrating that the EP2 receptor mediates PGE2-induced arterial vasodilation. EP2-/- mice also developed profound salt-sensitive hypertension, establishing a required role in blood-pressure homeostasis. Targeted gene disruption (EP2-/- mice), intravenous PGE2 infusion, blood pressure measurement, high-salt diet challenge Nature medicine High 9930871
1999 EP2 (PTGER2) knockout mice exhibit reduced litter sizes due to a pre-implantation defect involving impaired ovulation and dramatically reduced fertilization, establishing a required role for EP2 signaling in female fertility. Targeted gene disruption (EP2-/- mice), pregnancy day 2 and day 5 analysis of embryo implantation, ovulation, and fertilization Nature medicine High 9930871
2000 EP2 receptor (PTGER2) mediates PGE2-induced bronchodilation: PGE2 inhalation inhibited methacholine-induced airway constriction in wild-type but not EP2-/- mice, and paradoxically increased constriction in EP2-/- animals. Targeted gene disruption (EP2-/- mice), barometric plethysmography, mechanically ventilated mouse lung-resistance measurements Journal of applied physiology High 10846038
2001 EP2 receptor expression is restricted to the outer and inner medulla (descending thin limb of Henle's loop and outer medullary vasa recta) in the rat kidney, and butaprost (EP2-selective agonist) dose-dependently raised cAMP in microdissected EP2-positive segments but not in EP2-negative collecting duct segments, establishing site-specific cAMP-mediated paracrine regulation of tubular transport and vascular resistance. RNase protection assay, RT-PCR on microdissected nephron segments, cAMP radioimmunoassay with butaprost stimulation American journal of physiology. Renal physiology High 11352840
2003 EP2 receptor (PTGER2) stimulates Tcf/β-catenin-mediated transcriptional activity primarily through cAMP-dependent PKA, whereas EP4 additionally uses PI3K; EP2 does not activate ERK1/2 or induce EGR-1, distinguishing its downstream signaling from that of EP4. Tcf reporter assay, PKA inhibitor studies, PI3K inhibitor studies, ERK phosphorylation assay in transfected cells Life sciences Medium 14607241
2004 Activation of EP2 receptor (PTGER2) is neuroprotective in NMDA toxicity and oxygen-glucose deprivation paradigms via cAMP/PKA signaling; pharmacological blockade of PKA reversed EP2-mediated neuroprotection. Genetic deletion of EP2 significantly increased cerebral infarction in the MCAO stroke model. Dispersed neuron cultures, organotypic hippocampal cultures, PKA inhibition, EP2-/- mouse MCAO model with infarct volume measurement The Journal of neuroscience High 14715958
2005 EP2 receptor (PTGER2) is required for COX-2-induced mammary hyperplasia: bigenic MMTV-COX-2;Ep2-/- mice showed strongly suppressed precocious mammary development and hyperplasia, accompanied by reduced amphiregulin expression and reduced cAMP. EP2 agonist treatment of mammary tumor cells induced amphiregulin mRNA in a PKA-dependent manner, establishing a PGE2→EP2→cAMP/PKA→amphiregulin signaling axis driving mammary epithelial cell growth. Genetic bigenic mouse model (MMTV-COX-2 × EP2-/-), cAMP assay in mammary glands, EP2-selective agonist (CAY10399) treatment, amphiregulin RT-PCR, PKA inhibitor studies Cancer research High 15930264
2007 EP2 receptor (PTGER2) mediates a positive feedback loop in skin: PGE2 via EP2 activates PKA/CREB signaling to induce COX-2 expression and PGE2 production; EP2 knockout mice showed reduced COX-2 and PGE2 after TPA treatment, while EP2 transgenic mice showed increased COX-2 and CREB phosphorylation. Adenylate cyclase inhibitor blocked EP2-driven cell proliferation. EP2 knockout and transgenic mice, TPA/PGE2 treatment, COX-2 immunoblot, CREB phosphorylation assay, adenylate cyclase inhibitor (SQ22536), primary keratinocyte cultures Carcinogenesis High 17277233
2007 PTGER2 is epigenetically silenced in neuroblastoma cells (especially those with MYCN amplification) via DNA methylation, histone H3/H4 deacetylation, and H3K9 methylation at the promoter. Restoration of PTGER2 expression by transfection enabled EP2-agonist butaprost to increase cAMP, inhibit cell growth, and induce apoptosis via cAMP-dependent pathway. Bisulfite sequencing, ChIP for histone modifications, siRNA knockdown, stable/transient transfection, butaprost treatment, cAMP assay, cell growth and apoptosis assays Oncogene High 17533365
2010 DNA hypermethylation of the PTGER2 promoter, driven by increased Akt signaling, causes reduced EP2 expression and PGE2 resistance in fibrotic fibroblasts from humans and mice with pulmonary fibrosis. Treatment with DNA methylation inhibitors or DNMT-specific siRNA decreased PTGER2 methylation, restored EP2 expression, and rescued PGE2 responsiveness. Bisulfite sequencing, DNMT siRNA, DNA methylation inhibitors (5-aza-2'-deoxycytidine, zebularine), EP2 mRNA/protein quantification, PGE2 functional assays, Akt pathway analysis The American journal of pathology High 20889571
2010 Exogenous PGE2 or an EP2 receptor agonist completely counteracted the pro-fibrogenic effects (increased proliferation and matrix synthesis) caused by increased matrix stiffness in lung fibroblasts, demonstrating that EP2 is the receptor through which PGE2 maintains fibroblast quiescence and opposes fibrosis. Polyacrylamide hydrogel culture system with tunable stiffness, EP2-selective agonist treatment, fibroblast proliferation and matrix synthesis assays The Journal of cell biology Medium 20733059
2011 PGE2 suppresses Sclerostin (Sost) expression in osteoblastic cells via the EP2 receptor (PTGER2) through a cAMP/PKA pathway, leading to increased Wnt/TCF target gene expression (Axin2, Tcf3). EP2-selective agonists mimicked PGE2, and siRNA knockdown of Ptger2 prevented PGE2-induced Sost repression. EP2-selective agonists, siRNA knockdown of Ptger2, cAMP/PKA pathway inhibitors, RT-PCR for Sost/Axin2/Tcf3, osteoblastic UMR106.01 cell line PloS one High 21436889
2013 PGE2 acting through PTGER2 on porcine and human trophoblast cells promotes cell adhesion to extracellular matrix via integrin αVβ3, with signaling through MEK/MAPK and estrogen receptor. Blockade with EP2 antagonist AH6809, ITGAVB3 antibody, or MEK inhibition abolished PGE2-induced adhesion. RT-PCR and protein expression during implantation, butaprost treatment, EP2 antagonist (AH6809), integrin antibody, MEK inhibitor, FAK and ICAM-1 immunoblot in porcine and human trophoblast cells Endocrinology High 23861370
2013 EP2 activation promotes tumor cell growth and migration via a β-arrestin-dependent, G-protein-independent pathway in addition to the canonical cAMP-PKA pathway, expanding the known signaling repertoire of PTGER2. Review citing functional studies with EP2 agonists, β-arrestin pathway analysis Trends in pharmacological sciences Low 23796953
2014 The transcription factor RORC directly silences PTGER2 transcription in human Th17 cells by binding to the PTGER2 promoter; reduced RORC binding in MS patient Th17 cells results in higher EP2 levels, increased IFN-γ and GM-CSF, and a pathogenic Th17 phenotype. Overexpression of EP2 in healthy Th17 cells recapitulated the inflammatory gene program. ChIP-seq (RORγt binding to Ptger2/PTGER2 promoter), RORC siRNA knockdown, EP2 overexpression in human Th17 cells, comparison of healthy vs. MS patient cells The Journal of clinical investigation High 24812667
2014 PGE2 inhibits IL-10 production in brain microglia through the EP2 receptor via a β-arrestin-dependent, cAMP-independent pathway. EP2 genetic disruption abolished PGE2-mediated IL-10 suppression; EP2-selective agonist butaprost mimicked the effect; β-arrestin-1 or -2 deficiency also abolished the suppression. Primary neuron-glia cultures, EP2-/- mice, butaprost and other EP agonists, cAMP pathway inhibitors, β-arrestin-1/2 knockout microglia, IL-10 ELISA Molecular neurobiology High 25218510
2010 EP2 receptor signaling inhibits matrix metalloproteinase 13 (MMP-13) expression in human osteoarthritic chondrocytes via a cAMP/PKA pathway, and also suppresses other catabolic factors (MMP-1, MMP-3, ADAMTS5, IL-1β, TNF-α) without affecting cell viability. EP2 was identified as the major EP receptor in osteoarthritic cartilage. siRNA screen of 114 genes, butaprost (EP2 agonist) treatment ± IL-1β ± COX-2 inhibitor, cAMP/PKA inhibitors, MMP-13 ELISA and RT-PCR, cell viability assay, RT-PCR of EP receptor subtypes in OA cartilage Annals of the rheumatic diseases High 20870807
2015 Intracellular EP2 (iEP2) in PC3 prostate cancer cells promotes cancer-related phenotypes (proliferation, adhesion, migration, invasion, angiogenesis in vitro) through an EGFR transactivation–HIF-1α axis; inhibition of the prostaglandin uptake transporter, EP2 antagonist, or HIF-1α knockdown prevented these effects. PGE2 induced PKA-sensitive DNA synthesis even in isolated nuclei containing functional EP2 receptors. Pharmacological inhibition of prostaglandin uptake transporter, EP2 antagonist, EGFR antagonist, siRNA knockdown of HIF-1α, nuclear isolation and DNA synthesis assay, migration/invasion/angiogenesis in vitro assays Cellular and molecular life sciences Medium 25828575
2012 PTGS2-derived PGE2 protects against STZ-induced diabetes via PTGER2 and PTGER4 receptors; combined knockout of PTGER2 and PTGER4 (but not single knockouts) dramatically enhanced STZ pathology. PTGER2/PTGER4 agonist treatment of PTGS-2-/- and wild-type mice partially restored β-cell function and protected against STZ-induced diabetes. PTGER2-/-, PTGER4-/-, PTGER2/PTGER4 double KO mice, pharmacological PTGER4 blockade in PTGER2-/- background, EP2/EP4 agonist rescue, blood glucose, insulin, and survival measurement Diabetes High 22522619
2019 In an adult inducible EP2 knockout model (ROSACreER;EP2lox/lox), EP2 deletion reduced stroke severity, myeloid cell brain trafficking, and neuronal injury after MCAO, contrasting with the congenital EP2-/- model; neuronal-specific EP2 deletion (Thy1Cre;EP2lox/lox) reduced cerebral ischemic injury, identifying neurons as a cell type in which EP2 promotes ischemic damage. Myeloid-specific EP2 knockdown (Cd11bCre;EP2lox/lox) attenuated post-stroke immune cell infiltration but did not reduce infarct volume. Cell-type-specific conditional KO mice (ROSACreER, Thy1Cre, Cd11bCre), MCAO stroke model, infarct volume, brain immune cell flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 31036664
2020 EP2 receptor on peripheral immune myeloid cells drives key deleterious consequences of status epilepticus: conditional deletion of EP2 in CD11b+ myeloid cells (but not microglia) abolished hippocampal IL-6 induction, prevented BBB breakdown (measured by cortical albumin), and accelerated behavioral recovery after pilocarpine SE. Systemic EP2 antagonism additionally blocked monocyte brain infiltration and was neuroprotective, going beyond what myeloid-specific deletion achieved. CD11b-Cre;EP2lox/lox conditional KO mice, pilocarpine status epilepticus model, IL-6 ELISA, cortical albumin measurement, behavioral scoring, systemic EP2 antagonist administration The Journal of neuroscience High 33293358
2007 PTGER2 (EP2) mediates progesterone synthesis and type 1 11β-HSD activity stimulated by PGE2 in human granulosa-lutein cells via cAMP signaling; the EP2-selective agonist butaprost stimulated both responses, and the mixed EP1/EP2 antagonist AH6809 (but not the EP1-selective antagonist SC19220 alone) completely abolished both PGE2-stimulated cAMP accumulation and progesterone synthesis. Human granulosa-lutein cell cultures, EP2 agonist (butaprost), selective EP1 antagonist (SC19220), mixed EP1/EP2 antagonist (AH6809), cAMP radioimmunoassay, progesterone RIA, 11β-HSD activity assay The Journal of endocrinology High 17761898
2004 PGE2 via EP2 receptor suppresses TNF-α-induced CCL27 production in human keratinocytes by inhibiting NF-κB activity through a cAMP-dependent pathway. EP2 agonist increased intracellular cAMP, and PKA inhibitor (H-89) partially blocked the inhibitory effect; combined EP1/EP2 and EP3 antagonism completely reversed PGE2-mediated suppression. Human keratinocyte cultures, EP2/EP3 selective agonists, EP antagonists, NF-κB luciferase reporter assay, cAMP ELISA, Ca2+ chelator (BAPTA/AM), H-89 PKA inhibitor, CCL27 ELISA and RT-PCR The Journal of allergy and clinical immunology High 15577845

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 COX-2 inhibitors. Lancet (London, England) 823 9929039
2000 COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 716 11135226
2010 Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression. The Journal of cell biology 646 20733059
2003 EP2 and EP4 prostanoid receptor signaling. Life sciences 365 14607241
1999 Salt-sensitive hypertension and reduced fertility in mice lacking the prostaglandin EP2 receptor. Nature medicine 326 9930871
2004 Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. The Journal of neuroscience : the official journal of the Society for Neuroscience 312 14715958
2003 An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proceedings of the National Academy of Sciences of the United States of America 143 12748385
2008 Resveratrol directly targets COX-2 to inhibit carcinogenesis. Molecular carcinogenesis 140 18381589
2013 Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends in pharmacological sciences 134 23796953
1993 Cloning and expression of the EP2 subtype of human receptors for prostaglandin E2. Biochemical and biophysical research communications 125 8250933
2006 S100B binding to RAGE in microglia stimulates COX-2 expression. Journal of leukocyte biology 122 17023559
2011 Biology of Cox-2: an application in cancer therapeutics. Current drug targets 120 21443470
2010 Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. The American journal of pathology 119 20889571
2003 The role and regulation of COX-2 during viral infection. Viral immunology 111 14733733
2008 Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. The Journal of biological chemistry 105 18534982
2004 COX-2 inhibition and lung cancer. Seminars in oncology 105 15179623
2022 PGE2-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment. Cell reports 100 35675777
2010 COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Current opinion in investigational drugs (London, England : 2000) 100 20047157
2007 Function of COX-2 and prostaglandins in neurological disease. Journal of molecular neuroscience : MN 99 17901552
2005 New insights into COX-2 biology and inhibition. Brain research. Brain research reviews 96 15850674
2008 COX-2 inhibition in schizophrenia and major depression. Current pharmaceutical design 93 18537668
2008 Complexity of COX-2 gene regulation. Biochemical Society transactions 89 18482003
2005 The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia. Cancer research 88 15930264
1999 The role of COX-2 in intestinal cancer. Annals of the New York Academy of Sciences 80 10668484
2008 S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 77 18650379
2013 Mechanistic aspects of COX-2 expression in colorectal neoplasia. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 76 22893198
2020 COX-2 in liver fibrosis. Clinica chimica acta; international journal of clinical chemistry 70 32184095
2006 The potential and rationale for COX-2 inhibitors in lung cancer. Anti-cancer agents in medicinal chemistry 68 16712449
2000 EP(2) receptor mediates bronchodilation by PGE(2) in mice. Journal of applied physiology (Bethesda, Md. : 1985) 68 10846038
2018 COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization. Current molecular pharmacology 67 29468988
2015 Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis. Proceedings of the National Academy of Sciences of the United States of America 66 26199416
2020 COX-2-PGE2-EPs in gynecological cancers. Archives of gynecology and obstetrics 62 32363546
2005 Transcriptional Control of COX-2 via C/EBPbeta. Arteriosclerosis, thrombosis, and vascular biology 62 15681294
2013 Prostanoid receptor EP2 as a therapeutic target. Journal of medicinal chemistry 61 24279689
2005 Prostaglandins as mediators of COX-2 derived carcinogenesis in gastrointestinal tract. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 61 16247189
2006 COX-2 and atherosclerosis. Journal of cardiovascular pharmacology 60 16785826
2002 COX-2 inhibitors and their role in gynecology. Obstetrical & gynecological survey 60 12447099
2001 Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney. American journal of physiology. Renal physiology 60 11352840
2018 COX-2 induces oncogenic micro RNA miR655 in human breast cancer. Scientific reports 55 29321644
2007 COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation. The Journal of experimental medicine 54 17724132
2016 Cerebroprotection by the neuronal PGE2 receptor EP2 after intracerebral hemorrhage in middle-aged mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 53 26746866
2011 Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression. PloS one 52 21436889
1997 Detection of EP2, EP4, and FP receptors in human ciliary epithelial and ciliary muscle cells. Biochemical pharmacology 52 9214685
2012 Transactivation of EGFR by LPS induces COX-2 expression in enterocytes. PloS one 51 22675459
2008 Current status of COX-2 inhibitors. Mini reviews in medicinal chemistry 50 18220987
2000 COX-2 and the kidneys. Current pharmaceutical design 50 11102561
2012 Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. Trends in molecular medicine 49 22425675
2019 PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 48 31036664
2003 COX-2 and colorectal cancer. Current pharmaceutical design 48 14529404
2005 Positive feedback regulation of COX-2 expression by prostaglandin metabolites. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 47 15883739
2007 Epigenetic silencing of prostaglandin E receptor 2 (PTGER2) is associated with progression of neuroblastomas. Oncogene 44 17533365
2012 iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Experimental cell research 42 22683859
2017 HNE as an inducer of COX-2. Free radical biology & medicine 41 28192229
2014 Lead optimization studies of cinnamic amide EP2 antagonists. Journal of medicinal chemistry 41 24773616
1993 Stimulatory (EP1 and EP3) and inhibitory (EP2) prostaglandin E2 receptors in isolated ileal smooth muscle cells. European journal of pharmacology 41 7689467
2014 The PGE2-EP2-mast cell axis: an antiasthma mechanism. Molecular immunology 40 24768319
2011 TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 40 21566012
2008 Expression of 15-PGDH is downregulated by COX-2 in gastric cancer. Carcinogenesis 40 18174234
2004 Extracellular calcium induces COX-2 in osteoblasts via a PKA pathway. Biochemical and biophysical research communications 39 15325243
2007 Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin. Carcinogenesis 38 17277233
1990 EP3, but not EP2, FP, or TP prostanoid-receptor stimulation may reduce intraocular pressure. Investigative ophthalmology & visual science 38 2176184
2001 Is COX-2 inhibition a panacea for cancer prevention? International journal of cancer 37 11745453
2018 Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review). International journal of molecular medicine 36 29956743
2013 Autocrine and paracrine mechanisms of prostaglandin E₂ action on trophoblast/conceptus cells through the prostaglandin E₂ receptor (PTGER2) during implantation. Endocrinology 36 23861370
2004 Prostaglandin E(2) suppresses CCL27 production through EP2 and EP3 receptors in human keratinocytes. The Journal of allergy and clinical immunology 36 15577845
2014 Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. The Journal of clinical investigation 35 24812667
2007 COX-2: friend or foe? Current pharmaceutical design 34 17584101
2006 Prostaglandin E2 receptor subtype 2 (EP2) null mice are protected against murine lung tumorigenesis. Anticancer research 33 16886605
2015 Mucin 1 Regulates Cox-2 Gene in Pancreatic Cancer. Pancreas 32 26035123
2014 COX-2 Inhibitors and Gastric Cancer. Gastroenterology research and practice 32 25371669
2020 Targeting prostaglandin receptor EP2 for adjunctive treatment of status epilepticus. Pharmacology & therapeutics 30 32088247
2001 COX-2 inhibition and prevention of cancer. Best practice & research. Clinical gastroenterology 30 11566043
2020 Effects of the Selective EP2 Receptor Agonist Omidenepag on Adipocyte Differentiation in 3T3-L1 Cells. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics 29 31934812
2014 Development of second generation EP2 antagonists with high selectivity. European journal of medicinal chemistry 29 24937185
2010 The PGE2 EP2 receptor and its selective activation are beneficial against ischemic stroke. Experimental & translational stroke medicine 29 20615245
2005 Roles of LPA3 and COX-2 in implantation. Trends in endocrinology and metabolism: TEM 29 16226033
2002 Review article: COX-2, prostanoids and colon cancer. Alimentary pharmacology & therapeutics 29 11966530
2020 Peripheral Myeloid Cell EP2 Activation Contributes to the Deleterious Consequences of Status Epilepticus. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 33293358
2019 HIV-1 infection increases microRNAs that inhibit Dicer1, HRB and HIV-EP2, thereby reducing viral replication. PloS one 28 30682089
2013 Involvement of the prostaglandin E receptor EP2 in paeoniflorin-induced human hepatoma cell apoptosis. Anti-cancer drugs 28 23069790
2013 Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists. ACS medicinal chemistry letters 28 23914286
2010 Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes. Annals of the rheumatic diseases 28 20870807
2002 Polyamine-mediated post-transcriptional regulation of COX-2. Biochimie 28 12457568
2014 Prostaglandin E₂ receptor EP2 mediates Snail expression in hepatocellular carcinoma cells. Oncology reports 27 24626807
2007 Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. Biochemical and biophysical research communications 26 17555711
2005 Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 16507399
2024 Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors. Cell reports. Medicine 25 38242120
2014 PGE2 Inhibits IL-10 Production via EP2-Mediated β-Arrestin Signaling in Neuroinflammatory Condition. Molecular neurobiology 25 25218510
2003 Mucosal repair and COX-2 inhibition. Current pharmaceutical design 25 14529401
2013 Characterization of prostaglandin E2 receptors (EP2, EP4) in the horse oviduct. Animal reproduction science 24 24035156
2001 Analgesia and COX-2 inhibition. Clinical and experimental rheumatology 24 11695255
2012 PTGS-2-PTGER2/4 signaling pathway partially protects from diabetogenic toxicity of streptozotocin in mice. Diabetes 23 22522619
2007 PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11beta-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa lutein cells. The Journal of endocrinology 23 17761898
2004 Cardiovascular and renovascular implications of COX-2 inhibition. Current pharmaceutical design 23 14965323
2000 Paracetamol-inhibitable COX-2. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 23 11192935
2015 Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. Cellular and molecular life sciences : CMLS 22 25828575
2014 Prostaglandin E2 prevents hyperosmolar-induced human mast cell activation through prostanoid receptors EP2 and EP4. PloS one 22 25329458
2023 Tetrandrine Represses Inflammation and Attenuates Osteoarthritis by Selective Inhibition of COX-2. Current medical science 21 37204627
2023 PGE2-EP2/EP4 signaling elicits mesoCAR T cell immunosuppression in pancreatic cancer. Frontiers in immunology 21 37457723
2008 The role of COX-2 in heart pathology. Cardiovascular & hematological agents in medicinal chemistry 21 18220723