Genomes and Genes
Summary: Cell surface receptors that bind prostaglandins with high affinity and trigger intracellular changes which influence the behavior of cells. Prostaglandin receptor subtypes have been tentatively named according to their relative affinities for the endogenous prostaglandins. They include those which prefer prostaglandin D2 (DP receptors), prostaglandin E2 (EP1, EP2, and EP3 receptors), prostaglandin F2-alpha (FP receptors), and prostacyclin (IP receptors).
- Ota T, Aihara M, Narumiya S, Araie M. The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci. 2005;46:4159-63 pubmed..The prostanoid FP receptor plays a crucial role in the mechanism of early IOP lowering of all commercially available prostaglandin analogues. ..
- Kostenis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol Med. 2006;12:148-58 pubmed..Here, we examine the roles of DP and CRTH2 in the orchestration of complex inflammatory processes, and discuss their importance as emerging targets for the treatment of asthma and inflammatory diseases. ..
- Crowston J, Lindsey J, Morris C, Wheeler L, Medeiros F, Weinreb R. Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice. Invest Ophthalmol Vis Sci. 2005;46:4571-7 pubmed..An intact FP receptor gene is critical to the IOP response to bimatoprost in the mouse eye. ..
- Karanam B, Madeira M, Bradley S, Wenning L, Desai R, Soli E, et al. Absorption, metabolism, and excretion of [(14)C]MK-0524, a prostaglandin D(2) receptor antagonist, in humans. Drug Metab Dispos. 2007;35:1196-202 pubmed..Therefore, in humans, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces. ..
- Yoshimura Uchiyama C, Iikura M, Yamaguchi M, Nagase H, Ishii A, Matsushima K, et al. Differential modulation of human basophil functions through prostaglandin D2 receptors DP and chemoattractant receptor-homologous molecule expressed on Th2 cells/DP2. Clin Exp Allergy. 2004;34:1283-90 pubmed..The effects of PGD2 on longevity imply a mechanism(s) other than via DP or CRTH2/DP2. CRTH2/DP2 on basophils may afford opportunities for therapeutic targeting in allergic inflammation. ..
- Gyles S, Xue L, Townsend E, Wettey F, Pettipher R. A dominant role for chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) in mediating chemotaxis of CRTH2+ CD4+ Th2 lymphocytes in response to mast cell supernatants. Immunology. 2006;119:362-8 pubmed..These data suggest that PGD2, or closely related metabolites of arachidonic acid, produced from mast cells may play a central role in the activation of CRTH2+ CD4+ Th2 lymphocytes through a CRTH2-dependent mechanism. ..
- Almishri W, Cossette C, Rokach J, Martin J, Hamid Q, Powell W. Effects of prostaglandin D2, 15-deoxy-Delta12,14-prostaglandin J2, and selective DP1 and DP2 receptor agonists on pulmonary infiltration of eosinophils in Brown Norway rats. J Pharmacol Exp Ther. 2005;313:64-9 pubmed..The potent in vitro DP2 receptor agonist 15R-methyl-PGD2 is also very active in vivo and should be a useful tool in examining the role of this receptor. ..
- Sales K, List T, Boddy S, Williams A, Anderson R, Naor Z, et al. A novel angiogenic role for prostaglandin F2alpha-FP receptor interaction in human endometrial adenocarcinomas. Cancer Res. 2005;65:7707-16 pubmed..Finally, we confirmed that PGF2alpha could potentiate angiogenesis in endometrial adenocarcinoma explants by transactivation of the EGFR and induction of VEGF mRNA expression. ..
- Wehbrink D, Hassig M, Ritter N, Zerbe H, Bleul U, Boos A. Immunohistochemical demonstration of cyclooxygenase-2 (COX-2) and prostaglandin receptors EP2 and FP expression in the bovine intercaruncular uterine wall around term. Anim Reprod Sci. 2008;106:241-54 pubmed..EP2 remains rather unchanged during the peripartal period. COX-2 and FP thus contribute via changes in amount and distribution to mechanisms associated with parturition. ..
- Xue L, Gyles S, Wettey F, Gazi L, Townsend E, Hunter M, et al. Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol. 2005;175:6531-6 pubmed
- Park G, Christman J. Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol. 2006;290:L797-805 pubmed..These data have suggested a number of cell-specific, pathway-specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases. ..
- Spik I, Brénuchon C, Angeli V, Staumont D, Fleury S, Capron M, et al. Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse. J Immunol. 2005;174:3703-8 pubmed..Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy. ..
- Mandal A, Zhang Z, Ray R, Choi M, Chowdhury B, Pattabiraman N, et al. Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med. 2004;199:1317-30 pubmed..We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian airways to repress allergen-induced inflammatory responses. ..
- Moore M, Peebles R. Update on the role of prostaglandins in allergic lung inflammation: separating friends from foes, harder than you might think. J Allergy Clin Immunol. 2006;117:1036-9 pubmed..This review summarizes the current literature on the role of PGs and PG receptors in allergic lung inflammation. ..
- Pettipher R, Hansel T, Armer R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 2007;6:313-25 pubmed..We also discuss recent progress in the discovery and development of selective antagonists of these receptors. ..
- Sales K, Grant V, Jabbour H. Prostaglandin E2 and F2alpha activate the FP receptor and up-regulate cyclooxygenase-2 expression via the cyclic AMP response element. Mol Cell Endocrinol. 2008;285:51-61 pubmed publisher..These data indicate that PGE(2) and PGF(2alpha) biosynthesized locally within endometrial adenocarcinomas can regulate tumor cell function in an autocrine/paracrine manner via the FP receptor. ..
- Dishy V, Liu F, Ebel D, Atiee G, Royalty J, Reilley S, et al. Effects of aspirin when added to the prostaglandin D2 receptor antagonist laropiprant on niacin-induced flushing symptoms. J Clin Pharmacol. 2009;49:416-22 pubmed publisher..All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone...
- Sandig H, Andrew D, Barnes A, Sabroe I, Pease J. 9alpha,11beta-PGF2 and its stereoisomer PGF2alpha are novel agonists of the chemoattractant receptor, CRTH2. FEBS Lett. 2006;580:373-9 pubmed
- Ulven T, Kostenis E. Minor structural modifications convert the dual TP/CRTH2 antagonist ramatroban into a highly selective and potent CRTH2 antagonist. J Med Chem. 2005;48:897-900 pubmed..This is the first selective CRTH2 antagonist described to date, and should prove highly valuable in further elucidating the biological significance of CRTH2. ..
- Pettipher R. The roles of the prostaglandin D(2) receptors DP(1) and CRTH2 in promoting allergic responses. Br J Pharmacol. 2008;153 Suppl 1:S191-9 pubmed..The role played by CRTH2 in promoting the production of Th2 cytokines and IgE make antagonism of this receptor a particularly attractive approach to the treatment of chronic allergic disease. ..
- Hata A, Lybrand T, Marnett L, Breyer R. Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005;67:640-7 pubmed..Together, these results reveal structural features of arylacetic acid NSAIDs that may be exploited for the development of selective CRTH2 ligands. ..
- Hata A, Breyer R. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004;103:147-66 pubmed..The precise roles prostaglandin receptors play in physiologic and pathologic settings are determined by multiple factors including cellular context,..
- Lai E, De Lepeleire I, Crumley T, Liu F, Wenning L, Michiels N, et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther. 2007;81:849-57 pubmed publisher..In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation. ..
- Paolini J, Mitchel Y, Reyes R, Kher U, Lai E, Watson D, et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 2008;101:625-30 pubmed publisher..LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients...
- Chevalier E, Stock J, Fisher T, Dupont M, Fric M, Fargeau H, et al. Cutting edge: chemoattractant receptor-homologous molecule expressed on Th2 cells plays a restricting role on IL-5 production and eosinophil recruitment. J Immunol. 2005;175:2056-60 pubmed..These results suggest a nonredundant role of CRTH2 in restricting eosinophilia and allergic response in vivo. ..
- Cheng K, Wu T, Wu K, Sturino C, Metters K, Gottesdiener K, et al. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. Proc Natl Acad Sci U S A. 2006;103:6682-7 pubmed..These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans...
- Luster A, Tager A. T-cell trafficking in asthma: lipid mediators grease the way. Nat Rev Immunol. 2004;4:711-24 pubmed..However, as we discuss here, the recent molecular identification of leukotriene and prostaglandin receptors, as well as the generation of mice that are genetically deficient in them, has revealed that two of these ..
- Lai E, Wenning L, Crumley T, De Lepeleire I, Liu F, de Hoon J, et al. Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist. Clin Pharmacol Ther. 2008;83:840-7 pubmed..Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg. ..
- Shiraishi Y, Asano K, Nakajima T, Oguma T, Suzuki Y, Shiomi T, et al. Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor. J Pharmacol Exp Ther. 2005;312:954-60 pubmed..These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD(2)-related airway inflammation. ..
- Mathiesen J, Christopoulos A, Ulven T, Royer J, Campillo M, Heinemann A, et al. On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2006;69:1441-53 pubmed..A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs. ..
- Woodward D, Krauss A, Wang J, Protzman C, Nieves A, Liang Y, et al. Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris. Br J Pharmacol. 2007;150:342-52 pubmed..The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2alpha and PGE2-glyceryl ester. ..
- Wallace A, Sales K, Catalano R, Anderson R, Williams A, Wilson M, et al. Prostaglandin F2alpha-F-prostanoid receptor signaling promotes neutrophil chemotaxis via chemokine (C-X-C motif) ligand 1 in endometrial adenocarcinoma. Cancer Res. 2009;69:5726-33 pubmed publisher..In conclusion, our results show a novel PGF(2alpha)-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis. ..
- Maccubbin D, Koren M, Davidson M, Gavish D, Pasternak R, Macdonell G, et al. Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am J Cardiol. 2009;104:74-81 pubmed publisher..In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN. ..
- Benyo Z, Gille A, Kero J, Csiky M, Suchánková M, Nusing R, et al. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005;115:3634-40 pubmed..Our data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE(2) and PGD(2), most likely from immune cells of the skin. ..
- Van Hecken A, Depre M, De Lepeleire I, Thach C, Oeyen M, Van Effen J, et al. The effect of MK-0524, a prostaglandin D(2) receptor antagonist, on prostaglandin D (2)-induced nasal airway obstruction in healthy volunteers. Eur J Clin Pharmacol. 2007;63:135-41 pubmed..Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR. ..
- Muto A, Nishibe T, Miyauchi Y, Kondo Y, Yamamoto Y, Dardik A, et al. Prostaglandin receptors EP2 and IP are detectable in atherosclerotic arteries and plaques. Int Angiol. 2010;29:43-8 pubmed..These results suggest that receptor-selective PG agonists specifically target atherosclerotic arteries and therefore, may find potential application in the pharmacological management of patients with ASO. ..
- Sales K, Boddy S, Williams A, Anderson R, Jabbour H. F-prostanoid receptor regulation of fibroblast growth factor 2 signaling in endometrial adenocarcinoma cells. Endocrinology. 2007;148:3635-44 pubmed
- Huang J, Gao P, Mathias R, Yao T, Chen L, Kuo M, et al. Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability. Hum Mol Genet. 2004;13:2691-7 pubmed..11q is a strong candidate gene for asthma. ..
- Fujishima H, Fukagawa K, Okada N, Takano Y, Tsubota K, Hirai H, et al. Prostaglandin D2 induces chemotaxis in eosinophils via its receptor CRTH2 and eosinophils may cause severe ocular inflammation in patients with allergic conjunctivitis. Cornea. 2005;24:S66-S70 pubmed..PGD2 induced chemotaxis of eosinophils. Corneal epithelial damage might be caused by eosinophils, which are recruited by PGD2 secretion via CRTH2 expressed on eosinophils. ..
- Peri K, Quiniou C, Hou X, Abran D, Varma D, Lubell W, et al. THG113: a novel selective FP antagonist that delays preterm labor. Semin Perinatol. 2002;26:389-97 pubmed..05 g), and appeared healthy. This study describes an effective and selective noncompetitive FP antagonist, THG113, which significantly delays preterm delivery; this provides the basis for future investigations for its use in tocolysis. ..
- Boonyaprakob U, Gadsby J, Hedgpeth V, Routh P, Almond G. Cloning of pig prostaglandin F2alphaFP receptor cDNA and expression of its mRNA in the corpora lutea. Reproduction. 2003;125:53-64 pubmed..Direct luteal targets of PGF(2alpha) appear to be primarily large steroidogenic cells in this species. ..
- Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med. 2001;7:1048-51 pubmed
- Sales K, Jabbour H. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction. 2003;126:559-67 pubmed
- Kelley Hickie L, Kinsella B. EP1- and FP-mediated cross-desensitization of the alpha (alpha) and beta (beta) isoforms of the human thromboxane A2 receptor. Br J Pharmacol. 2004;142:203-21 pubmed
- Scott G, Leopardi S, Printup S, Malhi N, Seiberg M, Lapoint R. Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2alpha on melanocyte dendricity. J Invest Dermatol. 2004;122:1214-24 pubmed
- Hervé M, Angeli V, Pinzar E, Wintjens R, Faveeuw C, Narumiya S, et al. Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion. Eur J Immunol. 2003;33:2764-72 pubmed..We also suggest that DP1 is important in the Th1/Th2 balance of the immune response and in inflammatory reactions during infection. ..
- Fujino H, Regan J. Prostanoid receptors and phosphatidylinositol 3-kinase: a pathway to cancer?. Trends Pharmacol Sci. 2003;24:335-40 pubmed
- Inada M, Krane S. Targeting rheumatoid inflammation and joint destruction in the mouse. J Clin Invest. 2002;110:611-2 pubmed
- Hammad H, de Heer H, Soullie T, Hoogsteden H, Trottein F, Lambrecht B. Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol. 2003;171:3936-40 pubmed
- Woodward D, Krauss A, Chen J, Liang Y, Li C, Protzman C, et al. Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN 192024). J Pharmacol Exp Ther. 2003;305:772-85 pubmed..Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure. ..
- Fujitani Y, Kanaoka Y, Aritake K, Uodome N, Okazaki Hatake K, Urade Y. Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice. J Immunol. 2002;168:443-9 pubmed..These results indicate that PGD(2) plays an important role in late phase allergic reactions in the pathophysiology of bronchial asthma. ..
- Wright D, Abran D, Bhattacharya M, Hou X, Bernier S, Bouayad A, et al. Prostanoid receptors: ontogeny and implications in vascular physiology. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1343-60 pubmed..This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology. ..
- Sugimoto H, Shichijo M, Iino T, Manabe Y, Watanabe A, Shimazaki M, et al. An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J Pharmacol Exp Ther. 2003;305:347-52 pubmed..Our findings suggest that clinical efficacy of ramatroban may be in part mediated through its action on this Th2-, eosinophil-, and basophil-specific chemoattractant receptor. ..