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Characterization of the human cysteinyl leukotriene CysLT1 receptor

Nature volume 399, pages 789–793 (1999)Cite this article

Abstract

The cysteinyl leukotrienes—leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)—are important mediators of human bronchial asthma1,2,3,. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2 (refs 4,5,6). The CysLT1-selective antagonists, such as montelukast (Singulair)7,8,9,10, zafirlukast (Accolate)11 and pranlukast (Onon)12, are important in the treatment of asthma. Previous biochemical characterization of CysLT1 antagonists and the CysLT1 receptor has been in membrane preparations from tissues enriched for this receptor13. Here we report the molecular and pharmacological characterization of the cloned human CysLT1 receptor. 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. We detected CysLT1-receptor messenger RNA in spleen, peripheral blood leukocytes and lung. 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.

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Figure 1: Nucleotide and deduced amino-acid sequences of the HG55 (CysLT1) receptor.
Figure 2: Functional activation of HG55 (CysLT1) receptor in X.laevis cells.
Figure 3: Functional expression of HG55 (CysLT1) receptor in Cos-7 cells.
Figure 4: [3H]LTD4-specific binding to Cos-7 cell membranes expressing the HG55 (CysLT1) receptor.
Figure 5: Expression studies of the CysLT1 receptor.

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Acknowledgements

The authors thank M. E. Durieux (Dept. Anesthesiology, Univ. Virginia) for the use of his laboratory's oocyte recording equipment, D. Pettibone and R. Gould (Dept. Pharmacology, Merck & Co., West Point, Pennsylvania) for support to the MRL orphan GPCR project, and K. Clark for preparation of the figures. This work was supported in part by grants to K.R.L. from the National Institutes of Health. This paper is dedicated to the late P. J. Piper for her pioneering work in the pharmacological characterization of the cysteinyl leukotrienes.

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Authors and Affiliations

  1. Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, 22908, Virginia, USA

    Kevin R. Lynch, Dong-Soon Im, Shelley B. Hooks & Elizabeth Hosfield

  2. Department of Biochemistry and Molecular Biology, Merck, Frosst, Canada

    Gary P. O'Neill, Nicole Sawyer, Kathleen M. Metters, Nathalie Coulombe, Mark Abramovitz, Anne Chateauneuf, Rino Stocco, Gillian M. Greig & Stacia Kargman

  3. Department of Pharmacology, Sumneytown Pike, PO Box 4, West Point, 19486, Pennsylvania , USA

    David L. Williams Jnr & Anthony W. Ford-Hutchinson

  4. Department of Human Genetics, Merck & Co., Sumneytown Pike, PO Box 4, West Point , 19486, Pennsylvania, USA

    Qingyun Liu, David J. Figueroa, Zhizhen Zeng, Brett M. Connolly, Chang Bai, Christopher P. Austin, C. Thomas Caskey & Jilly F. Evans

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Correspondence to Jilly F. Evans.

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Lynch, K., O'Neill, G., Liu, Q. et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789–793 (1999). https://doi.org/10.1038/21658

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