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Atsushi Ichikawa - One of the best experts on this subject based on the ideXlab platform.
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Prostanoid receptor subtypes
Prostaglandins & Other Lipid Mediators, 2002Co-Authors: Kazuhito Tsuboi, Yukihiko Sugimoto, Atsushi IchikawaAbstract:Prostanoids are a group of lipid mediators that include the prostaglandins (PG) and thromboxanes (TX). Upon cell stimulation, Prostanoids are synthesized from arachidonic acid via the cyclooxygenase (COX) pathway and released outside the cells to exert various physiological and pathological actions in a variety of tissues and cells. The activities of Prostanoids are mediated by specific G protein-coupled receptors, which have been classified on the basis of pharmacological experiments into eight types and subtypes according to their responsiveness to selective agonists and antagonists. These Prostanoid receptors have been cloned from various species including human, and their distinct binding properties and signal transduction pathways have been characterized by analyses of cells expressing each receptor. Furthermore, the distribution patterns of Prostanoid receptor mRNAs have been determined in tissues and cells for various species. This information is useful for understanding the molecular basis of the pathophysiological actions of Prostanoids.
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altered pain perception and inflammatory response in mice lacking prostacyclin receptor
Nature, 1997Co-Authors: Takahiko Murata, Yukihiko Sugimoto, Atsushi Ichikawa, Fumitaka Ushikubi, Toshiyuki Matsuoka, Masakazu Hirata, Atsushi Yamasaki, Takashi Tanaka, N Yoshida, Akinori UenoAbstract:Prostanoids are a group of bioactive lipids working as local mediators1 and include D, E, F and I types of prostaglandins (PGs) and thromboxanes. Prostacyclin (PGI2) acts on platelets and blood vessels to inhibit platelet aggregation and to cause vasodilatation, and is thought to be important for vascular homeostasis2. Aspirin-like drugs, including indomethacin, which inhibit Prostanoid biosynthesis, suppress fever, inflammatory swelling and pain, and interfere with female reproduction, suggesting that Prostanoids are involved in these processes1,3, although it is not clear which Prostanoid is the endogenous mediator of a particular process. Prostanoids act on seven-transmembrane-domain receptors which are selective for each type4. Here we disrupt the gene for the prostacyclin receptor5 in mice by using homologous recombination. The receptor-deficient mice are viable, reproductive and normotensive. However, their susceptibility to thrombosis is increased, and their inflammatory and pain responses are reduced to the levels observed in indomethacin-treated wild-type mice. Our results establish that prostacyclin is an antithrombotic agent in vivo and provide evidence for its role as a mediator of inflammation and pain.
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molecular mechanisms of diverse actions of Prostanoid receptors
Biochimica et Biophysica Acta, 1995Co-Authors: Manabu Negishi, Yukihiko Sugimoto, Atsushi IchikawaAbstract:This review summarizes recent advances in the molecular characterization of Prostanoid receptors. Prostanoids exert versatile actions in diverse tissues and cells through specific cell surface receptors. Molecular biological studies revealed the primary structure of eight types and subtypes of Prostanoid receptor from various species. These include the thromboxane A2 receptor, prostacyclin receptor, prostaglandin (PG) F receptor, PGD receptor and four subtypes of PGE receptors. They are coupled to different signal transduction systems. In addition, multiple isoforms of PGE receptor EP3 subtype have been identified in various species. They are produced through alternative RNA splicing from a single gene and differ only in their carboxy-terminal tails. These isoforms differ in the efficiency of G protein activation, in the specificity of coupling to G proteins or in sensitivity to desensitization. This molecular characterization is useful for understanding the diverse physiological roles of Prostanoids.
Clifford J Woolf - One of the best experts on this subject based on the ideXlab platform.
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interleukin 1β mediated induction of cox 2 in the cns contributes to inflammatory pain hypersensitivity
Nature, 2001Co-Authors: Tarek A Samad, Stephen Poole, Kimberly A Moore, Adam Sapirstein, Sara Billet, Andrew Allchorne, Joseph V Bonventre, Clifford J WoolfAbstract:Inflammation causes the induction of cyclooxygenase-2 (Cox-2)1, leading to the release of Prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity2. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization)3, and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia4. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1β in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central Prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central Prostanoid production by inhibiting the interleukin-1β-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
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interleukin 1β mediated induction of cox 2 in the cns contributes to inflammatory pain hypersensitivity
Nature, 2001Co-Authors: Tarek A Samad, Stephen Poole, Kimberly A Moore, Adam Sapirstein, Sara Billet, Andrew Allchorne, Joseph V Bonventre, Clifford J WoolfAbstract:Inflammation causes the induction of cyclooxygenase-2 (Cox-2), leading to the release of Prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization), and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1beta in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central Prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central Prostanoid production by inhibiting the interleukin-1beta-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
Mark Abramovitz - One of the best experts on this subject based on the ideXlab platform.
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key structural features of prostaglandin e2 and Prostanoid analogs involved in binding and activation of the human ep1 Prostanoid receptor
Molecular Pharmacology, 2001Co-Authors: Mark Ungrin, Rino Stocco, Nicole Sawyer, Kathleen M Metters, Marieclaude Carriere, Danielle Denis, Sonia Lamontagne, Nathalie Tremblay, Mark AbramovitzAbstract:The structure-activity relationship (SAR) of prostaglandin (PG) E(2) at the human EP(1) Prostanoid receptor (designated hEP(1)) was examined via the binding and activation of this receptor by a series of 55 Prostanoids and analogs. Using clonal human embryonic kidney 293 cell lines expressing recombinant hEP(1), affinity (K(i)), potency (EC(50)), and efficacy data were obtained using a radioligand competitive binding assay and an aequorin-based calcium functional assay. All compounds behaved as full agonists (90-100% of the response elicited by PGE(2)) in this assay, and the correlation between the K(i) and EC(50) values was highly significant (R(2) = 0.86). The results from the SAR analysis can be summarized as follows: 1) the existence and configuration of hydroxyl groups at the 11 and 15 positions of PGE(2) and Prostanoid analog structures play a critical role in agonist activity; 2) the carboxyl group is also important for activity and modification of the carboxylic acid to various esters results in greatly reduced affinity and potency; 3) the activity of structures with moderate or weak potency can be enhanced by modification of the omega-tail; and 4) modifications to the ketone at the 9-position are better tolerated, with 9-deoxy-9-methylene-PGE(2) being the most potent agonist tested in the functional assay. The impact of other modifications on agonist potency is also discussed. The results from this study have identified, for the first time, the key structural features of PGE(2) and related Prostanoids and Prostanoid analogs necessary for activation of hEP(1).
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molecular cloning and characterization of the four rat prostaglandin e2 Prostanoid receptor subtypes
European Journal of Pharmacology, 1997Co-Authors: Yves Boie, Rino Stocco, Nicole Sawyer, Deborah Slipetz, Mark Ungrin, Frank Neuschaferrube, Gerhard Puschel, Kathleen M Metters, Mark AbramovitzAbstract:Abstract We have characterized the rat Prostanoid EP1, EP2, EP3α and EP4 receptor subtypes cloned from spleen, hepatocyte and/or kidney cDNA libraries. Comparison of the deduced amino acid sequences of the rat EP receptors with their respective homologues from mouse and human showed 91% to 98% and 82% to 89% identity, respectively. Radioreceptor binding assays and functional assays were performed on EP receptor expressing human embryonic kidney (HEK) 293 cells. The KD values obtained with prostaglandin E2 for the Prostanoid receptor subtypes EP1, EP2, EP3α and EP4 were approximately 24, 5, 1 and 1 nM, respectively. The rank order of affinities for various Prostanoids at the Prostanoid receptor subtypes EP2, EP3α and EP4 receptor subtypes was prostaglandin E2=prostaglandin E1>iloprost>prostaglandin F2α>prostaglandin D2>U46619. The rank order at the Prostanoid EP1 receptor was essentially the same except that iloprost had the highest affinity of the Prostanoids tested. Of the selective ligands, butaprost was selective for Prostanoid EP2, M&B28767 and sulprostone were selective for EP3α and enprostil displayed dual selectivity, interacting with both Prostanoid receptor subtypes EP1 and EP3α. All four receptors coupled to their predominant signal transduction pathways in HEK 293 cells. Notably, using a novel aequorin luminescence assay to monitor Prostanoid EP1 mediated increases in intracellular calcium, both iloprost and sulprostone were identified as partial agonists. Finally, by Northern blot analysis EP3 transcripts were most abundant in liver and kidney whereas Prostanoid EP2 receptor mRNA was expressed in spleen, lung and testis and Prostanoid EP1 receptor mRNA transcripts were predominantly expressed in the kidney. The rat Prostanoid EP1 probes also detected additional and abundant transcripts present in all the tissues examined. These were found to be related to the expression of a novel protein kinase gene and not the Prostanoid EP1 gene [Batshake, B., Sundelin, J., 1996. The mouse genes for the EP1 Prostanoid receptor and the novel protein kinase overlap. Biochem. Biophys. Res. Commun. 227, 1329–1333].
Matthew D Breyer - One of the best experts on this subject based on the ideXlab platform.
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physiological regulation of prostaglandins in the kidney
Annual Review of Physiology, 2008Co-Authors: Matthew D BreyerAbstract:Cyclooxygenase-derived Prostanoids exert complex and diverse functions within the kidney. The biological effect of each Prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and Prostanoid synthase for the synthesis of bioactive Prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived Prostanoids act in an autocrine or a paracrine fashion and can serve as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. Through these actions, Prostanoids play important roles in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived Prostanoids, particularly PGI2 and PGE2, play critical roles in maintaining blood pressure and renal function in volume-contracted states. Renal medullary COX2-derived Prostanoids appear to have an antihypertensive effect in individuals challenged with a high-salt diet. Loss of EP...
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Prostanoid receptors subtypes and signaling
Annual Review of Pharmacology and Toxicology, 2001Co-Authors: Richard M Breyer, Carey K Bagdassarian, Scott A Myers, Matthew D BreyerAbstract:Cyclooxygenases metabolize arachidonate to five primary Prostanoids: PGE2, PGF2α, PGI2, TxA2, and PGD2. These autacrine lipid mediators interact with specific members of a family of distinct G-protein-coupled Prostanoid receptors, designated EP, FP, IP, TP, and DP, respectively. Each of these receptors has been cloned, expressed, and characterized. This family of eight Prostanoid receptor complementary DNAs encodes seven transmembrane proteins which are typical of G-protein-coupled receptors and these receptors are distinguished by their ligand-binding profiles and the signal transduction pathways activated on ligand binding. Ligand-binding selectivity of these receptors is determined by both the transmembrane sequences and amino acid residues in the putative extracellular-loop regions. The selectivity of interaction between the receptors and G proteins appears to be mediated at least in part by the C-terminal tail region. Each of the EP1, EP3, FP, and TP receptors has alternative splice variants describe...
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g protein coupled Prostanoid receptors and the kidney
Annual Review of Physiology, 2001Co-Authors: Matthew D Breyer, Richard M BreyerAbstract:Renal cyclooxygenase 1 and 2 activity produces five primary Prostanoids: prostaglandin E2, prostaglandin F2alpha, prostaglandin I2, thromboxane A2, and prostaglandin D2. These lipid mediators interact with a family of distinct G protein-coupled Prostanoid receptors designated EP, FP, IP, TP, and DP, respectively, which exert important regulatory effects on renal function. The intrarenal distribution of these Prostanoid receptors has been mapped, and the consequences of their activation have been partially characterized. FP, TP, and EP1 receptors preferentially couple to an increase in cell calcium. EP2, EP4, DP, and IP receptors stimulate cyclic AMP, whereas the EP3 receptor preferentially couples to Gi, inhibiting cyclic AMP generation. EP1 and EP3 mRNA expression predominates in the collecting duct and thick limb, respectively, where their stimulation reduces NaCl and water absorption, promoting natriuresis and diuresis. The FP receptor is highly expressed in the distal convoluted tubule, where it may have a distinct effect on renal salt transport. Although only low levels of EP2 receptor mRNA are detected in the kidney and its precise intrarenal localization is uncertain, mice with targeted disruption of the EP2 receptor exhibit salt-sensitive hypertension, suggesting that this receptor may also play an important role in salt excretion. In contrast, EP4 receptor mRNA is predominantly expressed in the glomerulus, where it may contribute to the regulation of glomerular hemodynamics and renin release. The IP receptor mRNA is highly expressed near the glomerulus, in the afferent arteriole, where it may also dilate renal arterioles and stimulate renin release. Conversely, TP receptors in the glomerulus may counteract the effects of these dilator Prostanoids and increase glomerular resistance. At present there is little evidence for DP receptor expression in the kidney. These receptors act in a concerted fashion as physiological buffers, protecting the kidney from excessive functional changes during periods of physiological stress. Nonsteroidal anti-inflammatory drug (NSAID)-mediated cyclooxygenase inhibition results in the loss of these combined effects, which contributes to their renal effects. Selective Prostanoid receptor antagonists may provide new therapeutic approaches for specific disease states.
Tarek A Samad - One of the best experts on this subject based on the ideXlab platform.
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interleukin 1β mediated induction of cox 2 in the cns contributes to inflammatory pain hypersensitivity
Nature, 2001Co-Authors: Tarek A Samad, Stephen Poole, Kimberly A Moore, Adam Sapirstein, Sara Billet, Andrew Allchorne, Joseph V Bonventre, Clifford J WoolfAbstract:Inflammation causes the induction of cyclooxygenase-2 (Cox-2)1, leading to the release of Prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity2. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization)3, and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia4. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1β in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central Prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central Prostanoid production by inhibiting the interleukin-1β-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
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interleukin 1β mediated induction of cox 2 in the cns contributes to inflammatory pain hypersensitivity
Nature, 2001Co-Authors: Tarek A Samad, Stephen Poole, Kimberly A Moore, Adam Sapirstein, Sara Billet, Andrew Allchorne, Joseph V Bonventre, Clifford J WoolfAbstract:Inflammation causes the induction of cyclooxygenase-2 (Cox-2), leading to the release of Prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization), and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1beta in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central Prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central Prostanoid production by inhibiting the interleukin-1beta-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
