-
International Orthopaedics Dec 2007Prostaglandins, PGE(2) in particular, have diverse actions on various organs, including inflammation, bone healing, bone formation, embryo implantation, induction of... (Review)
Review
Prostaglandins, PGE(2) in particular, have diverse actions on various organs, including inflammation, bone healing, bone formation, embryo implantation, induction of labour and vasodilatation, among others. However, systemic side effects have limited their clinical utility. The pharmacological activities of PGE(2) are mediated through four G protein-coupled receptor subtypes, EP1-EP4. Recent studies have shown that EP2 and EP4 receptors play important roles in regulating bone formation and resorption. EP2 and EP4 receptor-selective agonists have been shown to stimulate local or systemic bone formation, augment bone mass and accelerate the healing of fractures or bone defects in animal models upon local or systemic administration, thus, potentially offering new therapeutic options for enhancing bone formation and bone repair in humans. This review will focus on the studies related to bone formation and bone healing in the EP receptor knockout (KO) mice and the EP2 or EP4 receptor-selective agonist treated animal models.
Topics: Animals; Dinoprostone; Mice; Mice, Knockout; Models, Animal; Osteogenesis; Rats; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 17593365
DOI: 10.1007/s00264-007-0406-x -
Postepy Higieny I Medycyny... May 2012Prevention and treatment of pathological inflammatory processes requires application of various classes of immune suppressors, such as calcineurin inhibitors, steroids... (Review)
Review
Prevention and treatment of pathological inflammatory processes requires application of various classes of immune suppressors, such as calcineurin inhibitors, steroids and non-steroid inhibitors of prostaglandin synthesis. However, each type of these immune suppressors causes less or more serious adverse side-effects. Exploration of the role played by prostanoids in the immune response and identification of functionally distinct prostaglandin E receptors (EP1-EP4) opened new perspectives in therapy of inflammation, autoimmunity and prevention of graft rejection. The EP4 receptor appeared to be an attractive target to affect manifestations of various pathological states by application of either agonists or antagonists of the receptor. This article presents a short overview of experimental approaches aimed at manipulation of signaling via EP2 and EP4 receptors that could have therapeutic utility.
Topics: Animals; Arthritis; Autoimmunity; Dinoprostone; Gastroenteritis; Graft Rejection; Humans; Hypersensitivity; Inflammation; Prostaglandins; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Reperfusion Injury
PubMed: 22706114
DOI: 10.5604/17322693.998859 -
Prostaglandins & Other Lipid Mediators Apr 2010This review presents an overview of the emerging field of prostaglandin signaling in neurological diseases, focusing on PGE(2) signaling through its four E-prostanoid... (Review)
Review
This review presents an overview of the emerging field of prostaglandin signaling in neurological diseases, focusing on PGE(2) signaling through its four E-prostanoid (EP) receptors. A large number of studies have demonstrated a neurotoxic function of the inducible cyclooxygenase COX-2 in a broad spectrum of neurological disease models in the central nervous system (CNS), from models of cerebral ischemia to models of neurodegeneration and inflammation. Since COX-1 and COX-2 catalyze the first committed step in prostaglandin synthesis, an effort is underway to identify the downstream prostaglandin signaling pathways that mediate the toxic effect of COX-2. Recent epidemiologic studies demonstrate that chronic COX-2 inhibition can produce adverse cerebrovascular and cardiovascular effects, indicating that some prostaglandin signaling pathways are beneficial. Consistent with this concept, recent studies demonstrate that in the CNS, specific prostaglandin receptor signaling pathways mediate toxic effects in brain but a larger number appear to mediate paradoxically protective effects. Further complexity is emerging, as exemplified by the PGE(2) EP2 receptor, where cerebroprotective or toxic effects of a particular prostaglandin signaling pathway can differ depending on the context of cerebral injury, for example, in excitotoxicity/hypoxia paradigms versus inflammatory-mediated secondary neurotoxicity. The divergent effects of prostaglandin receptor signaling will likely depend on distinct patterns and dynamics of receptor expression in neurons, endothelial cells, and glia and the specific ways in which these cell types participate in particular models of neurological injury.
Topics: Animals; Disease Models, Animal; Models, Biological; Nervous System Diseases; Receptors, Prostaglandin E
PubMed: 19808012
DOI: 10.1016/j.prostaglandins.2009.04.003 -
BioMed Research International 2013Prostanoids, including prostaglandins (PGs), thromboxanes (TXs), and prostacyclins, are synthesized from arachidonic acid (AA) by the action of Cyclooxygenase (COX)... (Review)
Review
Prostanoids, including prostaglandins (PGs), thromboxanes (TXs), and prostacyclins, are synthesized from arachidonic acid (AA) by the action of Cyclooxygenase (COX) enzymes. They are bioactive inflammatory lipid mediators that play a key role in immunity and immunopathology. Prostanoids exert their effects on immune and inflammatory cells by binding to membrane receptors that are widely expressed throughout the immune system and act at multiple levels in innate and adaptive immunity. The immunoregulatory role of prostanoids results from their ability to regulate cell-cell interaction, antigen presentation, cytokine production, cytokine receptor expression, differentiation, survival, apoptosis, cell-surface molecule levels, and cell migration in both autocrine and paracrine manners. By acting on immune cells of both systems, prostanoids and their receptors have great impact on immune regulation and play a pivotal role in connecting innate and adaptive immunity. This paper focuses on the immunobiology of prostanoid receptor signaling because of their potential clinical relevance for various disorders including inflammation, autoimmunity, and tumorigenesis. We mainly discuss the effects of major COX metabolites, PGD2, PGE2, their signaling during dendritic cell (DC)-natural killer (NK) reciprocal crosstalk, DC-T cell interaction, and subsequent consequences on determining crucial aspects of innate and adaptive immunity in normal and pathological settings.
Topics: Adaptive Immunity; Dendritic Cells; Dinoprostone; Humans; Immunity, Innate; Inflammation; Killer Cells, Natural; Prostaglandin D2; Prostaglandins; Receptors, Prostaglandin; Signal Transduction
PubMed: 24024207
DOI: 10.1155/2013/683405 -
Journal of Lipid Research Oct 2009Prostaglandin F(2alpha) is synthesized by prostaglandin F synthase, which exists in two types, prostaglandin F synthase I (PGFS I) and prostaglandin F synthase II (PGFS...
Prostaglandin F(2alpha) is synthesized by prostaglandin F synthase, which exists in two types, prostaglandin F synthase I (PGFS I) and prostaglandin F synthase II (PGFS II). Prostaglandin F(2alpha) binds to its specific receptor, FP. Our previous immunohistochemical study showed the distinct localization of prostaglandin F synthases in rat spinal cord. PGFS I exists in neuronal somata and dendrites in the gray substance, and PGFS II exists in ependymal cells and tanycytes surrounding the central canal. Both enzymes are also present in endothelial cells of blood vessels in the white and gray substances of the spinal cord. In this study, we found that FP localizes in neuronal somata and dendrites but not in ependymal cells, tanycytes, or endothelial cells. Immunohistochemical analysis of serial sections showed the colocalization of FP and PGFS I. FP immunoreactivity was intense in spinal laminae I and II of the dorsal horn, a connection site of pain transmission, and was similar to that of PGFS I in neuronal elements. These findings suggest that prostaglandin F(2alpha) synthesized in the neuronal somata and dendrites exert an autocrine action there.
Topics: Animals; Blotting, Western; Female; Hydroxyprostaglandin Dehydrogenases; Immunohistochemistry; Male; Rats; Receptors, Prostaglandin; Spinal Cord
PubMed: 19429887
DOI: 10.1194/jlr.M800543-JLR200 -
Proceedings of the National Academy of... Jul 2023To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize...
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, , re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, , 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, , 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that G-biased signaling, but not G activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-G, EP4-G, and EP4-G in complex with endogenous prostaglandin E (PGE)or two synthetic agonists and comparing with PGE-EP2-G structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the G/G transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their G/G coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for G/G coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
Topics: Dinoprostone; Signal Transduction; Receptors, Prostaglandin; GTP-Binding Protein alpha Subunits, Gs; Hormones; Receptors, Prostaglandin E, EP4 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype
PubMed: 37478163
DOI: 10.1073/pnas.2216329120 -
Physiological Reviews Oct 1999Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGI(2), and thromboxne A(2). They are... (Review)
Review
Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D(2), PGE(2), PGF(2alpha), PGI(2), and thromboxne A(2). They are synthesized and released upon cell stimulation and act on cells in the vicinity of their synthesis to exert their actions. Receptors mediating the actions of prostanoids were recently identified and cloned. They are G protein-coupled receptors with seven transmembrane domains. There are eight types and subtypes of prostanoid receptors that are encoded by different genes but as a whole constitute a subfamily in the superfamily of the rhodopsin-type receptors. Each of the receptors was expressed in cultured cells, and its ligand-binding properties and signal transduction pathways were characterized. Moreover, domains and amino acid residues conferring the specificities of ligand binding and signal transduction are being clarified. Information also is accumulating as to the distribution of these receptors in the body. It is also becoming clear for some types of receptors how expression of their genes is regulated. Furthermore, the gene for each of the eight types of prostanoid receptor has been disrupted, and mice deficient in each type of receptor are being examined to identify and assess the roles played by each receptor under various physiological and pathophysiological conditions. In this article, we summarize these findings and attempt to give an overview of the current status of research on the prostanoid receptors.
Topics: Animals; GTP-Binding Proteins; Gene Expression Regulation; Humans; Mice; Mice, Knockout; Prostaglandins; Receptors, Prostaglandin; Signal Transduction
PubMed: 10508233
DOI: 10.1152/physrev.1999.79.4.1193 -
American Journal of Hypertension Oct 2012Prostaglandin E(2) (PGE(2)) is a major prostanoid with a wide variety of biological activities. PGE(2) can influence blood pressure (BP) both positively and negatively.... (Review)
Review
Prostaglandin E(2) (PGE(2)) is a major prostanoid with a wide variety of biological activities. PGE(2) can influence blood pressure (BP) both positively and negatively. In particular, centrally administered PGE(2) induces hypertension whereas systemic administration of PGE(2) produces a hypotensive effect. These physiologically opposing effects are generated by the existence of multiple EP receptors, namely EP(1-4), which are G protein-coupled receptors with distinct signaling properties. This review highlights the distinct roles of PGE(2) in BP regulation and the involvement of specific EP receptor subtypes.
Topics: Animals; Blood Pressure; Dinoprostone; Humans; Kidney; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 22695507
DOI: 10.1038/ajh.2012.67 -
American Journal of Physiology. Renal... Apr 2021Local or systemic inflammation can severely impair urinary bladder functions and contribute to the development of voiding disorders in millions of people worldwide.... (Review)
Review
Local or systemic inflammation can severely impair urinary bladder functions and contribute to the development of voiding disorders in millions of people worldwide. Isoprostanes are inflammatory lipid mediators that are upregulated in the blood and urine by oxidative stress and may potentially induce detrusor overactivity. The aim of the present study was to investigate the effects and signal transduction of isoprostanes in human and murine urinary bladders in order to provide potential pharmacological targets in detrusor overactivity. Contraction force was measured with a myograph in murine and human urinary bladder smooth muscle (UBSM) ex vivo. Isoprostane 8-iso-PGE and 8-iso-PGF evoked dose-dependent contraction in the murine UBSM, which was abolished in mice deficient in the thromboxane prostanoid (TP) receptor. The responses remained unaltered after removal of the mucosa or incubation with tetrodotoxin. Smooth muscle-specific deletion of Gα protein or inhibition of Rho kinase by Y-27632 decreased the contractions. In Gα-knockout mice, responses were reduced and in the presence of Y-27632 abolished completely. In human UBSM, the TP agonist U-46619 evoked dose-dependent contractions. Neither atropine nor the purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid decreased the effect, indicating that TP receptors directly mediate detrusor muscle contraction. 8-iso-PGE and 8-iso-PGF evoked dose-dependent contraction in the human UBSM, and these responses were abolished by the TP antagonist SQ-29548 and were decreased by Y-27632. Our results indicate that isoprostanes evoke contraction in murine and human urinary bladders, an effect mediated by the TP receptor. The G-Rho-Rho kinase pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target in detrusor overactivity. Voiding disorders affect millions of people worldwide. Inflammation can impair urinary bladder functions and contribute to the development of detrusor overactivity. The effects and signal transduction of inflammatory lipid mediator isoprostanes were studied in human and murine urinary bladders ex vivo. We found that isoprostanes evoke contraction, an effect mediated by thromboxane prostanoid receptors. The G-Rho-Rho kinase signaling pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target.
Topics: Animals; Humans; Isoprostanes; Muscle, Smooth, Vascular; Prostaglandin Antagonists; Prostaglandins; Receptors, Prostaglandin; Receptors, Thromboxane
PubMed: 33491563
DOI: 10.1152/ajprenal.00400.2020 -
Drug News & Perspectives 2008Prostaglandin D(2) (PGD(2)) is produced by mast cells, Th2 lymphocytes and dendritic cells and causes activation of Th2 lymphocytes, eosinophils and basophils through a... (Review)
Review
Prostaglandin D(2) (PGD(2)) is produced by mast cells, Th2 lymphocytes and dendritic cells and causes activation of Th2 lymphocytes, eosinophils and basophils through a high-affinity interaction with the G protein-coupled receptor chemoattractant homologous receptor expressed on Th2 cells (CRTH2, also known as DP(2)). Activation of CRTH2 induces chemotaxis of Th2 lymphocytes and eosinophils and has the unusual property of promoting cytokine production by Th2 lymphocytes in the absence of allergen or co-stimulation. The ability of supernatants from immunologically activated mast cells to activate Th2 cells and eosinophils is mediated by CRTH2. This receptor also plays an important role in amplifying allergic responses through paracrine activation of Th2 cells. Pharmacological blockade or genetic ablation of CRTH2 is associated with a reduction in airways inflammation and reduced levels of mucus, Th2 cytokines and immunoglobulin E. The central role played by CRTH2 in mediating these effects suggests that antagonism of this receptor is an attractive approach to the treatment of chronic allergic disease.
Topics: Aminoquinolines; Animals; Anti-Allergic Agents; Asthma; Basophils; Carbazoles; Dendritic Cells; Disease Models, Animal; Eosinophils; Humans; Hypersensitivity; Indoleacetic Acids; Mast Cells; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Signal Transduction; Sulfonamides; Th2 Cells
PubMed: 18836589
DOI: 10.1358/dnp.2008.21.6.1246831