A Novel Hepatointestinal Leukotriene B4 Receptor

Wang, Suke; Gustafson, Eric L.; Pang, Lei; Qiao, Xudong; Behan, Jiang; Maguire, Maureen; Bayne, Marvin L.; Laz, Thomas M.

doi:10.1074/jbc.m004512200

Cited by 68 publications

(29 citation statements)

References 39 publications

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“…The presence of the leukotriene and cannabinoid receptors in this lipid cluster may seem strange at first. Leukotrienes are however also eicosanoids, which clarifies the position of the leukotriene B 4 and cysteinyl-leukotriene receptors in this cluster [37,38]. In addition, arachidonic acid is the common precursor for eicosanoids and two derivatives of arachidonic acid, anandamide and 2-arachidonylglycerol, both of which are endogenous ligands ('endocannabinoids') of the cannabinoid receptors.…”

Section: Resultsmentioning

confidence: 99%

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

et al. 2010

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BackgroundG protein-coupled receptors (GPCRs) represent a family of well-characterized drug targets with significant therapeutic value. Phylogenetic classifications may help to understand the characteristics of individual GPCRs and their subtypes. Previous phylogenetic classifications were all based on the sequences of receptors, adding only minor information about the ligand binding properties of the receptors. In this work, we compare a sequence-based classification of receptors to a ligand-based classification of the same group of receptors, and evaluate the potential to use sequence relatedness as a predictor for ligand interactions thus aiding the quest for ligands of orphan receptors.ResultsWe present a classification of GPCRs that is purely based on their ligands, complementing sequence-based phylogenetic classifications of these receptors. Targets were hierarchically classified into phylogenetic trees, for both sequence space and ligand (substructure) space. The overall organization of the sequence-based tree and substructure-based tree was similar; in particular, the adenosine receptors cluster together as well as most peptide receptor subtypes (e.g. opioid, somatostatin) and adrenoceptor subtypes. In ligand space, the prostanoid and cannabinoid receptors are more distant from the other targets, whereas the tachykinin receptors, the oxytocin receptor, and serotonin receptors are closer to the other targets, which is indicative for ligand promiscuity. In 93% of the receptors studied, de-orphanization of a simulated orphan receptor using the ligands of related receptors performed better than random (AUC > 0.5) and for 35% of receptors de-orphanization performance was good (AUC > 0.7).ConclusionsWe constructed a phylogenetic classification of GPCRs that is solely based on the ligands of these receptors. The similarities and differences with traditional sequence-based classifications were investigated: our ligand-based classification uncovers relationships among GPCRs that are not apparent from the sequence-based classification. This will shed light on potential cross-reactivity of GPCR ligands and will aid the design of new ligands with the desired activity profiles. In addition, we linked the ligand-based classification with a ligand-focused sequence-based classification described in literature and proved the potential of this method for de-orphanization of GPCRs.

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Section: Resultsmentioning

confidence: 99%

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

et al. 2010

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“…In the GPLP, the selective BLT 1 receptor partial agonist U‐75302 ( Yokomizo et al , 2000 ; Wang et al , 2000 ) had a significant contractile activity, but only partially inhibited the contractions induced by LTB 4 . Moreover, the preferential BLT 1 receptor agonist 20‐COOH‐LTB 4 ( Wang et al , 2000 ) induced contractions that were abolished by U‐75302. Taken together, these results suggest a functional BLT 1 receptor in the GPLP.…”

Section: Discussionmentioning

confidence: 99%

“…The BLT receptors consist of two receptor subtypes, BLT 1 and BLT 2 , which can be pharmacologically recognised using receptor antagonists, where ONO‐4057 has been reported to inhibit both BLT receptors, whereas U‐75302 is a selective BLT 1 receptor antagonist ( Lawson et al , 1989 ; Kishikawa et al , 1992 ; Yokomizo et al , 1997 ,2000). In addition, the ω ‐oxidised metabolite of LTB 4 , 20‐COOH‐LTB 4 , has been reported to be a preferential BLT 1 receptor agonist ( Wang et al , 2000 ). Using these tools, the receptors mediating the contractile effects of LTB 4 in the guinea‐pig lung were assessed in the present study.…”

Section: Introductionmentioning

confidence: 99%

The contractile action of leukotriene B₄ in the guinea‐pig lung involves a vascular component

Sakata

Dahlén

Bäck

2004

British J Pharmacology

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1 Leukotriene B 4 (LTB 4 ) is a potent leukocyte chemoattractant, acting on specific receptors, BLT receptors. The aim of this study was to examine the mechanism of action of LTB 4 in the guinea-pig lung, using strips of lung parenchyma (GPLP), spirals of trachea (GPT) and bronchus (GPB) and rings of pulmonary artery (GPPA). Mechanical responses were studied in organ baths, and mediator release was assessed using enzyme immuno assay. 2 LTB 4 induced similar contractions of GPLP and GPPA, whereas LTB 4 had only small contractile effects in GPT and GPB. In addition, the contractile response to LTB 4 was reproduced in the human pulmonary artery. 3 In the GPLP, the unselective BLT receptor antagonist ONO-4057 abolished the contractions induced by LTB 4 , whereas the selective BLT 1 receptor antagonist U-75302 only partly inhibited the LTB 4 -induced contractions. In the GPPA, both antagonists abolished the response to LTB 4 . 4 The effect of LTB 4 in GPPA and GPLP was indirect and mediated by the release of thromboxane A 2 and histamine, as supported by selective pharmacologic interventions and measurements of thromboxane B 2 and histamine in the organ baths. 5 In conclusion, the results indicate a new biological function of LTB 4 , namely to constrict isolated pulmonary arteries. Moreover, the findings suggest that the LTB 4 -induced contractions of GPPA were mediated by a BLT 1 receptor, whereas BLT 2 receptor activation accounted for a major part of the contraction of GPLP, making the latter preparation a suitable assay for BLT 2 receptors.

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“…It appears to signal leucocytes through a seven transmembrane-spaning G protein-coupled receptors (Huang et al, 1998). Two classes of LTB 4 receptors have been identified: LTB 4 receptor-1 (LTB 4 -R1) and LTB 4 receptor-2 (LTB 4 R-2) (Wang et al, 2000). The two receptors differ in their affinity and specificity for LTB 4 .…”

Section: Ltb 4 Receptormentioning

confidence: 99%

“…The main targets of LTB 4 are leucocytes where it induces chemotaxis, immigration and activation. Hence, LTB 4 is an important chemical mediator involved in inflammatory diseases such as RA, asthma and IBD (Wang et al, 2000). It appears to signal leucocytes through a seven transmembrane-spaning G protein-coupled receptors (Huang et al, 1998).…”

Section: Ltb 4 Receptormentioning

confidence: 99%

The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets?

2006

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Leukotrienes (LTs), a family of lipid mediators, play a key role in the pathogenesis of inflammation. They are synthesized in the leucocytes from arachidonic acid (AA) via the actions of 5-lipoxygenase (5-LO). LTs are classified into two classes: LTB(4) and cysteinyl LTs (CysLTs). LTB(4) is one of the most potent chemoattractant mediators of inflammation. It exerts its actions through a seven transmembrane-spaning G protein receptors, LTB4 R-1 and LTB4 R-2. CysLTs (LTC(4), LTD(4), and LTE(4)) are potent bronchoconstrictors that play an important role in asthma. They induce their actions through G protein coupled receptors, CysLT R-1 and CysLT R-2. LTs are involved in the pathogenesis of inflammatory disorders specially asthma, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Therefore, LTs modifiers, LTs inhibitors or antagonists, represent important therapeutic advance in the management of inflammatory diseases. Zileuton, zafirlukast and montelukast are LTs modifiers that are approved to use for the treatment of inflammatory disorders.

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A Novel Hepatointestinal Leukotriene B4 Receptor

Cited by 68 publications

References 39 publications

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

The contractile action of leukotriene B₄ in the guinea‐pig lung involves a vascular component

The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets?

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A Novel Hepatointestinal Leukotriene B4 Receptor

Cited by 68 publications

References 39 publications

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

A novel chemogenomics analysis of G protein-coupled receptors (GPCRs) and their ligands: a potential strategy for receptor de-orphanization

The contractile action of leukotriene B4 in the guinea‐pig lung involves a vascular component

The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets?

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The contractile action of leukotriene B₄ in the guinea‐pig lung involves a vascular component