Characterization of Mouse Cysteinyl Leukotriene Receptors mCysLT1 and mCysLT2

Ogasawara, Haruhiko; Ishii, Satoshi; Yokomizo, Takehiko; Kakinuma, Takashi; Komine, Mayumi; Tamaki, Kunihiko; Shimizu, Takao; Izumi, Tohru

doi:10.1074/jbc.m109447200

Cited by 53 publications

(26 citation statements)

References 34 publications

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“…ϩ RNA was hybridized with [ 32 P]dCTP-labeled probes of human p2y 9 /GPR23 and human ␤-actin, as described previously (16). The washed membrane was subjected to autoradiography for 4 days (p2y 9 /GPR23) or 3 h (␤-actin).…”

Section: Methodsmentioning

confidence: 99%

Identification of p2y9/GPR23 as a Novel G Protein-coupled Receptor for Lysophosphatidic Acid, Structurally Distant from the Edg Family

Noguchi

Ishii

Shimizu

2003

Journal of Biological Chemistry

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520

425

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Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. LPA has been widely considered to elicit its biological functions through three types of G protein-coupled receptors, Edg-2 (endothelial cell differentiation gene-2)/LPA 1 /vzg-1 (ventricular zone gene-1), Edg-4/LPA 2 , and Edg-7/LPA 3 . We identified an orphan G protein-coupled receptor, p2y 9 /GPR23, as the fourth LPA receptor (LPA 4 ). Membrane fractions of RH7777 cells transiently expressing p2y 9 /GPR23 displayed a specific binding for 1-oleoyl-LPA with a K d value of around 45 nM. Competition binding and reporter gene assays showed that p2y 9 /GPR23 preferred structural analogs of LPA with a rank order of 1-oleoyl-> 1-stearoyl-> 1-palmitoyl-> 1-myristoyl-> 1-alkyl-> 1-alkenyl-LPA. In Chinese hamster ovary cells expressing p2y 9 /GPR23, 1-oleoyl-LPA induced an increase in intracellular Ca 2؉ concentration and stimulated adenylyl cyclase activity. Quantitative real-time PCR demonstrated that mRNA of p2y 9 /GPR23 was significantly abundant in ovary compared with other tissues. Interestingly, p2y 9 /GPR23 shares only 20 -24% amino acid identities with Edg-2/LPA 1 , Edg-4/LPA 2 , and Edg-7/LPA 3 , and phylogenetic analysis also shows that p2y 9 /GPR23 is far distant from the Edg family. These facts suggest that p2y 9 /GPR23 has evolved from different ancestor sequences from the Edg family.

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Section: Methodsmentioning

confidence: 99%

Identification of p2y9/GPR23 as a Novel G Protein-coupled Receptor for Lysophosphatidic Acid, Structurally Distant from the Edg Family

Noguchi

Ishii

Shimizu

2003

Journal of Biological Chemistry

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520

425

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“…RT-PCR for cysLT 1 receptor was conducted as previously described (31). The sense primer was 5Ј-CAA CGA ACT ATC CAC CTT CAC C-3Ј, and the antisense primer was 5Ј-AGC CTT CTC CTA AAG TTT CCA C-3Ј.…”

Section: Rt-pcrmentioning

confidence: 99%

A Novel Role of Cysteinyl Leukotrienes to Promote Dendritic Cell Activation in the Antigen-Induced Immune Responses in the Lung

Okunishi

Dohi

Nakagome

et al. 2004

The Journal of Immunology

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Although the critical role of cysteinyl leukotrienes (cysLTs) in the inflammation, especially eosinophilic lung inflammation, in asthma has been well documented, their role in the early stage of Ag-specific immune response has not been completely clarified. In the present study, with a mouse model of asthma and in vitro studies we demonstrated that cysLTs potentiated dendritic cell (DC) functions such as Ag-presenting capacity and cytokine production. The cysLT-1 receptor antagonist (LTRA) strongly suppressed the activation of these DC functions and led to inhibition of subsequent not only Th2, but also Th1, responses in the early stage of immune response. Moreover, treatment with LTRA during the early stage of the immune response potently suppressed the development of Ag inhalation-induced eosinophilic airway inflammation, mucus production, and airway hyper-reactivity in vivo. Treatment with LTRA significantly increased PGE2 production in the lung, and treatment with the cyclooxygenase inhibitor indomethacin abolished LTRA’s suppressive effect on DCs and deteriorated the Th2 and Th1 responses and airway inflammation. With in vitro studies, we also confirmed that cysLTs production by DCs increased with LPS stimulation, and that LTRA directly suppressed the alloantigen-presenting capacity of DCs. 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.

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“…We and others have reported that the mouse CysLT 1 receptor can function as a receptor for LTD 4 in transfected cells with a ligand preference similar to that of the human CysLT 1 receptor (19 -22). The mouse CysLT 2 receptor exhibits a ligand profile of LTC 4 Ն LTD 4 Ͼ Ͼ LTE 4 (22,23). In contrast to the extensive studies on the functions of the CysLT 1 receptor (24,25), the functional characterization of the CysLT 2 receptor has been limited because of a lack of specific competitive antagonists.…”

mentioning

confidence: 99%

Targeted Gene Disruption Reveals the Role of the Cysteinyl Leukotriene 2 Receptor in Increased Vascular Permeability and in Bleomycin-induced Pulmonary Fibrosis in Mice

Beller

Maekawa

Friend

et al. 2004

Journal of Biological Chemistry

138

110

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The cysteinyl leukotrienes (cys-LTs) mediate both acute and chronic inflammatory responses in mice, as demonstrated by the attenuation of the IgE/antigen-mediated increase in microvascular permeability and of bleomycin-induced pulmonary fibrosis, respectively, in a strain with targeted disruption of leukotriene C 4 synthase to prevent cys-LT synthesis. Our earlier finding that the acute, but not the chronic, injury was attenuated in a strain with targeted disruption of the cysteinyl leukotriene 1 (CysLT 1 ) receptor suggested that the chronic injury might be mediated through the CysLT 2 receptor. Thus, we generated CysLT 2 receptor-deficient mice by targeted gene disruption. These mice developed normally and were fertile. The increased vascular permeability associated with IgE-dependent passive cutaneous anaphylaxis was significantly reduced in CysLT 2 receptor-null mice as compared with wild-type mice, whereas plasma protein extravasation in response to zymosan A-induced peritoneal inflammation was not altered. Alveolar septal thickening after intratracheal injection of bleomycin, characterized by interstitial infiltration with macrophages and fibroblasts and the accumulation of collagen fibers, was significantly reduced in CysLT 2 receptor-null mice as compared with the wild-type mice. The amounts of cys-LTs in bronchoalveolar lavage fluid after bleomycin injection were similar in the CysLT 2 receptor-null mice and the wildtype mice. 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.The cysteinyl leukotrienes (cys-LTs), 1 leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are lipid mediators (1, 2) that have been implicated in the pathobiology of allergic and asthmatic inflammatory responses on the basis of the efficacy of specific intervention with a biosynthetic inhibitor (3) or antagonists to a receptor subsequently shown to be the cysteinyl leukotriene 1 (CysLT 1 ) receptor (4). Two types of human receptors for cys-LTs, designated CysLT 1 receptor and CysLT 2 receptor, belonging to the seventransmembrane, G protein-coupled receptor family, were cloned and shown to be 38% homologous in their amino acid sequences (5-9). The rank order of affinities of the cys-LTs for the CysLT 1 and CysLT 2 receptors is LTD 4 Ͼ LTC 4 Ͼ LTE 4 Ͼ Ͼ LTB 4 and LTC 4 ϭ LTD 4 Ͼ Ͼ LTE 4 Ͼ Ͼ LTB 4 , respectively. The CysLT 1 receptor is expressed on airway smooth muscle, monocytes/ macrophages, eosinophils (5, 10, 11), a subset of neutrophils (11), mast cells (12, 13), and endothelial cells (14). The CysLT 2 receptor is expressed on monocyte/macrophages, airway smooth muscle, cardiac Purkinje cells, adrenal medulla cells, peripheral blood leukocytes, brain cells (7), eosinophils (11, 15), mast cells (16), and endothelial cells (17,18). We and others have reported that the mouse CysLT 1 receptor can function as a receptor for LTD 4 in transfected cells with a ligand preference similar to that of the...

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Characterization of Mouse Cysteinyl Leukotriene Receptors mCysLT1 and mCysLT2

Cited by 53 publications

References 34 publications

Identification of p2y9/GPR23 as a Novel G Protein-coupled Receptor for Lysophosphatidic Acid, Structurally Distant from the Edg Family

Identification of p2y9/GPR23 as a Novel G Protein-coupled Receptor for Lysophosphatidic Acid, Structurally Distant from the Edg Family

A Novel Role of Cysteinyl Leukotrienes to Promote Dendritic Cell Activation in the Antigen-Induced Immune Responses in the Lung

Targeted Gene Disruption Reveals the Role of the Cysteinyl Leukotriene 2 Receptor in Increased Vascular Permeability and in Bleomycin-induced Pulmonary Fibrosis in Mice

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