Genomes and Genes
Summary: Cell-surface receptors that bind LEUKOTRIENES with high affinity and trigger intracellular changes influencing the behavior of cells. The leukotriene receptor subtypes have been tentatively named according to their affinities for the endogenous leukotrienes LTB4; LTC4; LTD4; and LTE4.
- Hui Y, Cheng Y, Smalera I, Jian W, Goldhahn L, Fitzgerald G, et al. Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation. 2004;110:3360-6 pubmed..The development of EC-hCysLT2R mice has permitted detection of distinct vascular effects of CysLTs, which can be mediated via the CysLT2R in vivo. ..
- Okunishi K, Dohi M, Nakagome K, Tanaka R, Yamamoto K. A novel role of cysteinyl leukotrienes to promote dendritic cell activation in the antigen-induced immune responses in the lung. J Immunol. 2004;173:6393-402 pubmed..These results suggested that cysLTs potentiate DC functions both in vivo and in vitro, and that LTRA could be beneficial to suppress the initial immune response in many immune-mediated disorders beyond asthma. ..
- Steinke J, Borish L. Leukotriene receptors in rhinitis and sinusitis. Curr Allergy Asthma Rep. 2004;4:217-23 pubmed..Comprehensive inhibition of the proinflammatory activities of CysLTs might require either combination CysLT1 and CysLT2 receptor antagonists or inhibitors of the CysLT synthesis pathway. ..
- Woszczek G, Pawliczak R, Qi H, Nagineni S, Alsaaty S, Logun C, et al. Functional characterization of human cysteinyl leukotriene 1 receptor gene structure. J Immunol. 2005;175:5152-9 pubmed..Thus, cysLTs signaling through cysLT(1)R might contribute to inflammatory reactions by cooperating with IL-4 in enhanced CCL2 production in human monocytic cells. ..
- Tryselius Y, Nilsson N, Kotarsky K, Olde B, Owman C. Cloning and characterization of cDNA encoding a novel human leukotriene B(4) receptor. Biochem Biophys Res Commun. 2000;274:377-82 pubmed..Studies of intracellular calcium flow of transfected HeLa cells exposed to various leukotrienes showed that also the novel BLTR-like receptor can be activated by leukotriene B(4), and it is therefore tentatively named BLTR2. ..
- Maekawa A, Kanaoka Y, Lam B, Austen K. Identification in mice of two isoforms of the cysteinyl leukotriene 1 receptor that result from alternative splicing. Proc Natl Acad Sci U S A. 2001;98:2256-61 pubmed..Thus, the dominant mouse isoform with the N-terminal amino acid extension encoded by an additional exon has the same ligand response profile as the spliced form and the human receptor. ..
- Ohshima N, Nagase H, Koshino T, Miyamasu M, Yamaguchi M, Hirai K, et al. A functional study on CysLT(1) receptors in human eosinophils. Int Arch Allergy Immunol. 2002;129:67-75 pubmed..CysLTs induce migration and enhance degranulation in eosinophils via CysLT(1). Accordingly, interaction of CysLTs and CysLT(1) on eosinophils has the potential to play a prominent role in the pathophysiology of asthma. ..
- Bautz F, Denzlinger C, Kanz L, Mohle R. Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1. Blood. 2001;97:3433-40 pubmed..This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation. (Blood. 2001;97:3433-3440) ..
- Pillai S, Cousens D, Barnes A, Buckley P, Chiano M, Hosking L, et al. A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics. 2004;14:627-33 pubmed..Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy. ..
- Saito H, Morikawa H, Howie K, Crawford L, Baatjes A, Denburg E, et al. Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis. Immunology. 2004;113:246-52 pubmed..The anti-allergic effects of cysLT1-R antagonists are consistent with the concept that cysLTs and IL-5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation. ..
- Holgate S, Peters Golden M, Panettieri R, Henderson W. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clin Immunol. 2003;111:S18-34; discussion S34-6 pubmed
- Ciana P, Fumagalli M, Trincavelli M, Verderio C, Rosa P, Lecca D, et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J. 2006;25:4615-27 pubmed..In conclusion, the deorphanization of GPR17 revealed a dualistic receptor for two endogenous unrelated ligand families. These findings may lead to dualistic drugs of previously unexplored therapeutic potential. ..
- Capra V, Accomazzo M, Ravasi S, Parenti M, Macchia M, Nicosia S, et al. Involvement of prenylated proteins in calcium signaling induced by LTD4 in differentiated U937 cells. Prostaglandins Other Lipid Mediat. 2003;71:235-51 pubmed..In conclusion, in dU937 LTD4 signal transduction involves: (a) at least two pathways, one sensitive and one insensitive to PTx; (b) isoprenylated proteins, such as betagamma subunits and, possibly, a small G protein of the Ras family. ..
- Mamedova L, Capra V, Accomazzo M, Gao Z, Ferrario S, Fumagalli M, et al. CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors. Biochem Pharmacol. 2005;71:115-25 pubmed
- Peres C, Aronoff D, Serezani C, Flamand N, Faccioli L, Peters Golden M. Specific leukotriene receptors couple to distinct G proteins to effect stimulation of alveolar macrophage host defense functions. J Immunol. 2007;179:5454-61 pubmed
- Heise C, O Dowd B, Figueroa D, Sawyer N, Nguyen T, Im D, et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem. 2000;275:30531-6 pubmed
- Duroudier N, Sayers I, Castagna C, Fenech A, Halapi E, Swan C, et al. Functional polymorphism and differential regulation of CYSLTR1 transcription in human airway smooth muscle and monocytes. Cell Biochem Biophys. 2007;47:119-30 pubmed
- Kanaoka Y, Boyce J. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J Immunol. 2004;173:1503-10 pubmed
- Maekawa A, Kanaoka Y, Xing W, Austen K. Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors. Proc Natl Acad Sci U S A. 2008;105:16695-700 pubmed publisher..Our findings establish the existence of a third receptor, CysLT(E)R, that responds preferentially to LTE(4), the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention. ..
- Beller T, Maekawa A, Friend D, Austen K, Kanaoka Y. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J Biol Chem. 2004;279:46129-34 pubmed..Thus, in response to a particular pathobiologic event the CysLT(2) receptor can mediate an increase in vascular permeability in some tissues or promote chronic pulmonary inflammation with fibrosis. ..
- Capra V. Molecular and functional aspects of human cysteinyl leukotriene receptors. Pharmacol Res. 2004;50:1-11 pubmed..Molecular cloning of different CysLT receptor subtypes will certainly foster the development of new selective antagonists based on molecular modelling studies. ..
- Henderson W, Chiang G, Tien Y, Chi E. Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med. 2006;173:718-28 pubmed
- Arriba Mendez S, Sanz C, Isidoro Garcia M, Davild I, Laffond E, Horeno E, et al. 927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis. Pediatr Allergy Immunol. 2006;17:323-8 pubmed..Further studies are needed to confirm these findings. ..
- Hui Y, Funk C. Cysteinyl leukotriene receptors. Biochem Pharmacol. 2002;64:1549-57 pubmed..This review summarizes receptor cloning, ligand binding, expression, signaling, and functions in an effort to bridge early pharmacological studies to future studies at the molecular level. ..
- Sanz C, Isidro García M, Davila I, Moreno E, Laffond E, Lorente F. Analysis of 927T> C CYSLTRI and -444A > C LTC4S polymorphisms in patients with asthma. J Investig Allergol Clin Immunol. 2006;16:331-7 pubmed..Further studies are needed to confirm such an association. ..
- Woszczek G, Chen L, Nagineni S, Kern S, Barb J, Munson P, et al. Leukotriene D(4) induces gene expression in human monocytes through cysteinyl leukotriene type I receptor. J Allergy Clin Immunol. 2008;121:215-221.e1 pubmed..Our data show that CysLTs acting through CysLTR(1) can significantly influence the activation and migration of human monocytes and that these effects can be fully inhibited by CysLTR(1) antagonists. ..
- Spinozzi F, Russano A, Piattoni S, Agea E, Bistoni O, de Benedictis D, et al. Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes. Clin Exp Allergy. 2004;34:1876-82 pubmed..The induction of apoptosis in allergen-specific T cell population, as a final result, appears fundamental in the treatment of asthma. ..
- Lynch K, O Neill G, Liu Q, Im D, Sawyer N, Metters K, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999;399:789-93 pubmed..In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT1-receptor gene to the X chromosome. ..
- Beller T, Friend D, Maekawa A, Lam B, Austen K, Kanaoka Y. Cysteinyl leukotriene 1 receptor controls the severity of chronic pulmonary inflammation and fibrosis. Proc Natl Acad Sci U S A. 2004;101:3047-52 pubmed
- Jiang Y, Borrelli L, Bacskai B, Kanaoka Y, Boyce J. P2Y6 receptors require an intact cysteinyl leukotriene synthetic and signaling system to induce survival and activation of mast cells. J Immunol. 2009;182:1129-37 pubmed..Thus, CysLT1R and P2Y6 receptors, which are coexpressed on many cell types of innate immunity, reciprocally amplify one another's function in mast cells through endogenous ligands. ..
- Mohle R, Bautz F, Denzlinger C, Kanz L. Transendothelial migration of hematopoietic progenitor cells. Role of chemotactic factors. Ann N Y Acad Sci. 2001;938:26-34; discussion 34-5 pubmed..g., SDF-1). Trafficking of immature hematopoietic cells may require combined and interactive regulatory functions of these mediators. ..
- Nagata M, Saito K, Tsuchiya K, Sakamoto Y. Leukotriene D4 upregulates eosinophil adhesion via the cysteinyl leukotriene 1 receptor. J Allergy Clin Immunol. 2002;109:676-80 pubmed..LTD(4) generated from EOS or cells of some other type might contribute to the development of phenotypic change in airway EOS. ..
- Suzuki M, Kato M, Kimura H, Fujiu T, Morikawa A. Inhibition of human eosinophil activation by a cysteinyl leukotriene receptor antagonist (pranlukast; ONO-1078). J Asthma. 2003;40:395-404 pubmed..stimulation by platelet-activating factor or other mediators, and these cells themselves express cysteinyl leukotriene receptors. Pranlukast, a compound developed in Japan, antagonizes cysteinyl leukotriene receptors and inhibits ..
- Lotzer K, Spanbroek R, Hildner M, Urbach A, Heller R, Bretschneider E, et al. Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler Thromb Vasc Biol. 2003;23:e32-6 pubmed..Our data raise the possibility that MPhi-derived LTs differentially activate cysLT2-Rs via paracrine stimulation and cysLT1-Rs via autocrine and paracrine stimulation during inflammation and atherogenesis. ..
- Kim S, Yang E, Park H, Ye Y, Lee H, Park H. Differential contribution of the CysLTR1 gene in patients with aspirin hypersensitivity. J Clin Immunol. 2007;27:613-9 pubmed..013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiating two major aspirin hypersensitivity phenotypes. ..
- Ballerini P, Di Iorio P, Ciccarelli R, Caciagli F, Poli A, Beraudi A, et al. P2Y1 and cysteinyl leukotriene receptors mediate purine and cysteinyl leukotriene co-release in primary cultures of rat microglia. Int J Immunopathol Pharmacol. 2005;18:255-68 pubmed..In conclusion, the data of the present study suggest a cross talk between the purine and leukotriene systems in a possible autocrine/paracrine control of the microglia-mediated initiation and progression of an inflammatory response...
- Bandeira Melo C, Hall J, Penrose J, Weller P. Cysteinyl leukotrienes induce IL-4 release from cord blood-derived human eosinophils. J Allergy Clin Immunol. 2002;109:975-9 pubmed
- Thivierge M, Stankova J, Rola Pleszczynski M. Toll-like receptor agonists differentially regulate cysteinyl-leukotriene receptor 1 expression and function in human dendritic cells. J Allergy Clin Immunol. 2006;117:1155-62 pubmed..Our study demonstrates that some microbial agents can reduce the migration of dendritic cells in response to leukotrienes, with potential for differential involvement of these cells in allergic inflammation. ..
- Zhang J, Migita O, Koga M, Shibasaki M, Arinami T, Noguchi E. Determination of structure and transcriptional regulation of CYSLTR1 and an association study with asthma and rhinitis. Pediatr Allergy Immunol. 2006;17:242-9 pubmed..Our findings indicate that CYSLTR1 polymorphisms are not likely to be involved in the development of asthma/rhinitis, but it is possible that these polymorphisms could influence drug responses in individuals with atopic diseases. ..
- Asakura T, Ishii Y, Chibana K, Fukuda T. Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-beta. J Allergy Clin Immunol. 2004;114:310-5 pubmed..These data suggest that treatment with leukotriene receptor antagonists might prevent airway remodeling in patients with asthma. ..
- Duroudier N, Tulah A, Sayers I. Leukotriene pathway genetics and pharmacogenetics in allergy. Allergy. 2009;64:823-39 pubmed publisher..The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes. ..
- Sjöström M, Jakobsson P, Juremalm M, Ahmed A, Nilsson G, Macchia L, et al. Human mast cells express two leukotriene C(4) synthase isoenzymes and the CysLT(1) receptor. Biochim Biophys Acta. 2002;1583:53-62 pubmed..Moreover, the expression of the cognate receptor CysLT(1) suggests that these lipid mediators may be involved in autocrine signaling pathways regulating mast cell functions. ..
- Figueroa D, Breyer R, Defoe S, Kargman S, Daugherty B, Waldburger K, et al. Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med. 2001;163:226-33 pubmed..We also report the expression of CysLT1 receptor mRNA and protein in most peripheral blood eosinophils and pregranulocytic CD34+ cells, and in subsets of monocytes and B lymphocytes. ..
- Mellor E, Frank N, Soler D, Hodge M, Lora J, Austen K, et al. Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R. Proc Natl Acad Sci U S A. 2003;100:11589-93 pubmed
- Gronert K, Martinsson Niskanen T, Ravasi S, Chiang N, Serhan C. Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. Am J Pathol. 2001;158:3-9 pubmed
- Figueroa D, Borish L, Baramki D, Philip G, Austin C, Evans J. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin Exp Allergy. 2003;33:1380-8 pubmed..Our expression data highlight the potential of CysLT-modifying agents to treat both upper and lower airway symptoms in patients suffering from allergic rhinitis and asthma. ..
- Klotsman M, York T, Pillai S, Vargas Irwin C, Sharma S, van den Oord E, et al. Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics. 2007;17:189-96 pubmed..These findings require replication to establish validity and clinical utility. ..
- Reinhold S, Vitzthum H, Filbeck T, Wolf K, Lattas C, Riegger G, et al. Gene expression of 5-, 12-, and 15-lipoxygenases and leukotriene receptors along the rat nephron. Am J Physiol Renal Physiol. 2006;290:F864-72 pubmed..already been determined, the localization of lipoxygenases and leukotriene-forming enzymes together with leukotriene receptors in the kidney is less clear...
- Naik S, Billington C, Pascual R, Deshpande D, Stefano F, Kohout T, et al. Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling. J Biol Chem. 2005;280:8722-32 pubmed..These findings characterized the CysLT1R as the first G protein-coupled receptor identified to date in which PKC is the principal regulator of both rapid agonist-dependent internalization and rapid agonist-dependent desensitization. ..
- Di Capite J, Nelson C, Bates G, Parekh A. Targeting Ca2+ release-activated Ca2+ channel channels and leukotriene receptors provides a novel combination strategy for treating nasal polyposis. J Allergy Clin Immunol. 2009;124:1014-21.e1-3 pubmed publisher..Hence our results identify a new potential strategy for combating polyposis and mast cell-dependent allergies. ..
- Mellor E, Maekawa A, Austen K, Boyce J. Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci U S A. 2001;98:7964-9 pubmed
- Early S, Barekzi E, Negri J, Hise K, Borish L, Steinke J. Concordant modulation of cysteinyl leukotriene receptor expression by IL-4 and IFN-gamma on peripheral immune cells. Am J Respir Cell Mol Biol. 2007;36:715-20 pubmed..On circulating cells, expression of the leukotriene receptors is low, but in inflamed tissue the receptor number is dramatically increased...
- McMahon B, Mitchell D, Shattock R, Martin F, Brady H, Godson C. Lipoxin, leukotriene, and PDGF receptors cross-talk to regulate mesangial cell proliferation. FASEB J. 2002;16:1817-9 pubmed..These data elaborate on the profile of cell signaling events that underpin the anti-inflammatory and proresolution bioactions of LX. ..