Disease relevance of CYSLTR1

• Determination of structure and transcriptional regulation of CYSLTR1 and an association study with asthma and rhinitis [1].
• A strain with targeted disruption of the CysLT1 receptor gene is protected against the pathobiological insults that augment microvascular permeability, whereas a strain with targeted disruption of the CysLT2 receptor gene is protected against pulmonary fibrosis [2].
• Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas [3].
• 927T>C polymorphism of the cysteinyl-leukotriene type-1 receptor (CYSLTR1) gene in children with asthma and atopic dermatitis [4].
• Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin [5].

High impact information on CYSLTR1

• We describe the functional activation (calcium mobilization) of this receptor by LTD4 and LTC4, and competition for radiolabelled LTD4 binding to this receptor by the cysteinyl leukotrienes and three structurally distinct classes of CysLT1-receptor antagonists [6].
• The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), are important in the treatment of asthma [6].
• In normal human lung, expression of the CysLT1-receptor mRNA was confined to smooth muscle cells and tissue macrophages [6].
• We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung [6].
• Finally, we mapped the human CysLT1-receptor gene to the X chromosome [6].

Chemical compound and disease context of CYSLTR1

• Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonist [7].
• OBJECTIVE: The aim of this study is to determine whether montelukast, a LTD4 receptor antagonist, plus desloratadine, is more efficacious than desloratadine alone in the treatment of chronic urticaria [8].
• OBJECTIVE: We examined the effect of CysLT antagonists (pranlukast and MCI-826) on antigen inhalation-induced eosinophilia in peripheral blood and lung, and on IL-5 activity in serum during late increase of airway resistance (late asthmatic response, LAR) in sensitized guinea-pigs [9].
• A recent clinical study showed that combined antagonists loratadine (H1) and zafirlukast (CysLT1) were more effective against allergic bronchospasms than either drug alone [10].
• Mast cell histamine (HA) and cysteinyl leukotrienes (CysLT) account for most of the early phase bronchospasm in asthma [10].

Biological context of CYSLTR1

• The leukotriene modifying agents currently used to control bronchoconstriction and inflammation in asthmatic patients are CYSLTR1-specific leukotriene receptor antagonists [11].
• The promoter region of CYSLTR1 is from -665 to -30 bp relative to the transcription start site [1].
• The experiment of rapid amplification of cDNA end revealed that CYSLTR1 contains three exons and that the entire open reading frame is located in exon 3 [1].
• METHODS: Gene expression of CysLTR1 and CysLTR2 mRNAs in human peripheral blood eosinophils, neutrophils, monocytes and T lymphocytes has been measured by competitive reverse transcription-polymerase chain reactions using RNA or DNA competitors [12].
• To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls [13].

Anatomical context of CYSLTR1

• OBJECTIVE: To define the role of LT in human DC function, we studied the expression and function of the cysteinyl-leukotriene (CysLT) receptors during DC differentiation from monocytes and subsequent maturation [14].
• Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils [12].
• RESULTS: (a) When cellular levels of CysLTR1 mRNA were normalized to those of G3PDH mRNA, the relative concentration of CysLTR1 mRNA in eosinophils (43.8 +/- 37.2, n = 29) was significantly higher than that in neutrophils (18.7 +/- 23.3, n = 11), monocytes (0.93 +/- 1.1, n = 10) and T lymphocytes (3.4 +/- 2.4, n = 11) [12].
• (c) Human umbilical vein endothelial cells expressed CysLTR2 mRNA, but not CysLTR1 mRNA [12].
• The ratio of CysLTR1 mRNA to CysLTR2 mRNA was significantly lower in eosinophils (0.65 +/- 0.42, n = 12) than in neutrophils (6.9 +/- 4.9, n = 12), monocytes (1.8 +/- 0.9, n = 10) and T lymphocytes (4.5 +/- 5.7, n = 10) [12].

Associations of CYSLTR1 with chemical compounds

• Immature DCs and DCs matured with polyI:C, but not with LPS, responded to LTD(4) with a robust cytosolic calcium flux, which was prevented by the CysLT1 antagonist montelukast [14].
• For in situ hybridization study of human nasal mucosa, we used biotin-labelled oligonucleotides probes encoding human CysLT1 receptor cDNA [15].
• In addition, the study involved evaluation of a leukotriene E4 analogue, BAY u9773, suggested to inhibit responses which cannot be blocked by CysLT1-receptor antagonists [16].
• In guinea pig lung parenchyma, the effects of BAY u9773 and conventional cysteinyl leukotriene receptor antagonists (ICI 198,615, FPL 55,712) were more complex [16].
• In the guinea pig ileum, BAY u9773 but not the selective CysLT1 receptor antagonist ICI 198,615 inhibited the contractile response to leukotriene C4 in a fashion suggesting competitive antagonism [16].

Physical interactions of CYSLTR1

• A novel localization of the G-protein-coupled CysLT1 receptor in the nucleus of colorectal adenocarcinoma cells [17].

Regulatory relationships of CYSLTR1

• Two approaches to antileukotriene therapy have been developed: blocking their production by inhibiting the action of 5-lipoxygenase enzyme or blocking the CysLTR1 [18].
• The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells [5].
• A significantly greater proportion of CD33+ cells (55%) expressed CysLT1 receptor compared with CD123+ cells (11%) [19].
• The metabolic cascade involved in CysLT synthesis was not expressed in fibroblasts and could not be induced by IL-4 treatment [20].
• CysLT1 receptor antagonist montelukast and corticosteroid inhibit TGF-beta1 production at the mRNA and protein levels [21].

Other interactions of CYSLTR1

• 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 [22].
• Leukotriene C4 synthase (LTC4S) is the critical terminal pathway enzyme involved in regulation of cysteinyl leukotriene (CysLT) synthesis [23].
• RESULTS: When human BSMC were exposed to transforming growth factor (TGF)-beta, IL-13, or IFN-gamma, their expression of CysLT1 receptor was significantly augmented in a time- and concentration-dependent manner [24].
• Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU [25].
• Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion [26].

Analytical, diagnostic and therapeutic context of CYSLTR1

• Reverse transcriptase-polymerase chain reaction showed that there were multiple splice variants of CYSLTR1 and that the transcript expression patterns differed from tissues and cell types [1].
• In situ hybridization and immunocytochemical techniques were used to identify the mRNA and proteins for the CysLT1 and CysLT2 receptors [22].
• Thus, LTC(4) acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release [26].
• METHODS: Expression of CysLT1 receptor was measured by flow cytometry and immunofluorescence microscopy [24].
• In addition, the distribution of the CysLT1 receptor protein was studied by immunohistochemistry [15].

References