The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama, Utako; Iwatsubo, Kousaku; Umemura, Masanari; Fujita, Takayuki; Ishikawa, Yoshihiro

doi:10.1124/pr.112.007195

Cited by 227 publications

(280 citation statements)

References 531 publications

(718 reference statements)

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“…EP4 have been identified for the first time in the piglet saphenous vein [4], and it was observed to be insensitive to agonists of the other types of EP receptors (EP1, EP2, and EP3) [1]. The expression of EP4 receptor was found in a vast variety of tissues (e.g.…”

Section: Introductionmentioning

confidence: 97%

“…The expression of EP4 receptor was found in a vast variety of tissues (e.g. cardiovascular, immune, gastrointestinal, skeletal, cancer tissue) [1,5].…”

Section: Introductionmentioning

confidence: 99%

“…It is known from the specialty literature that many biological processes, like: bone and vascular remodeling, carcinogenesis, renal function, cardiac hypertrophy, gastrointestinal homeostasis, and reproductive function, are closely related to EP4 signaling [1]. EP4 receptor has, also, a major role in pain and inflammation induced by prostaglandin E2 (PGE2) mediator [2].…”

Section: Introductionmentioning

confidence: 99%

“…It was observed that both agonists and antagonists of EP4 receptor are responsible for the influence of various pathologic states [1]. In order to gain insight about the interaction patterns between EP4 receptor and its ligands (agonists and antagonists) the homology model of EP4 waspreviously built [6] and was used for docking experiments in this study.…”

Section: Introductionmentioning

confidence: 99%

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<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

Borota

Funar-Timofei

Crisan

2017

Proceedings of the 21st International Electronic Conference on Synthetic Organic Chemistry

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Abstract:In this work, a previously reported homology model of prostanoid EP4 was used for docking studies of potent EP4 ligands, in order to provide information about protein -ligand interaction patterns. Glide software, from the Schrödinger package, with XP option, was used for docking simulations. Among the amino acids residues from the EP4 binding site that made interactions with the ligands taken in our study, the key residue Ser285 (highlighted, also, in mutagenesis studies) was noted. The observed interactions between ligands and amino acid residues consist in several hydrogen bonds (e.g. with Thr175, His181, Ser95, Ser103, Asp311) and hydrophobic interactions (e.g. with Ala314, Tyr186). The outcome resulted from the docking studies led to a better understanding of how the agonists and antagonists bind in situ and may lead to the discovery of new active compounds.

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Section: Introductionmentioning

confidence: 97%

“…The expression of EP4 receptor was found in a vast variety of tissues (e.g. cardiovascular, immune, gastrointestinal, skeletal, cancer tissue) [1,5].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

Borota

Funar-Timofei

Crisan

2017

Proceedings of the 21st International Electronic Conference on Synthetic Organic Chemistry

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“…EP2 and EP4 are "relaxant" receptors coupled to stimulatory G proteins (Gs) mediating increases in intracellular cAMP Coleman et al, 1994;Honda et al, 1993;Narumiya and FitzGerald, 2001). Reports from 2000s show that they were also able to mediate transcriptional activation through e. g. phosphokinase A-dependent pathway for EP2 or phosphatidylinositol 3-kinase-dependent pathway and other pathways for EP4 that in the latter case was shown to bind to a Gi protein (Fujino and Regan, 2006;Fujino et al, 2005;Fujino et al, 2002) (reviewed in Yokoyama et al, 2013). EP3, the only constitutive "inhibitory" receptor in the prostanoid receptor family (Narumiya and FitzGerald, 2001), is the most abundant PGE2 receptor subtype in the brain (Sugimoto and Narumiya, 2007).…”

Section: Pge2 Receptorsmentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

et al. 2017

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The 2-series of prostaglandin E (PGE ) is regarded as a pro-cancer prostanoid, whereas the 1-series (PGE ) and the 3-series (PGE ) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE and PGE , but not PGE , exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)4 receptor-mediated signaling pathway. PGE , PGE and PGE function as full agonists in terms of G - and G -protein-mediated signaling. However, PGE and PGE function as partial agonists of T-cell factor (TCF)/β-catenin (β-cat)-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE or PGE almost completely reduces PGE -induced TCF/β-cat activity. These results provide a plausible reason why PGE and PGE function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.

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The Prostanoid EP4 Receptor and Its Signaling Pathway

Cited by 227 publications

References 531 publications

<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

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The Prostanoid EP4 Receptor and Its Signaling Pathway

Cited by 227 publications

References 531 publications

<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

<strong>MOLECULAR DOCKING STUDY OF THE INTERACTIONS OF PROSTANOID EP4 RECEPTOR WITH POTENT LIGANDS</strong>

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

PGE1 and E3 show lower efficacies than E2 to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

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PGE₁ and E₃ show lower efficacies than E₂ to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors