1. Department of Pharmacology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA
2. Department of Biochemistry and Molecular Biology, Merck Frosst Canada
3. Department of Pharmacology Sumneytown Pike, PO Box 4, West Point, Pennsylvania 19486, USA
4. Department of Human Genetics, Merck & Co.,Sumneytown Pike, PO Box 4, West Point , Pennsylvania 19486, USA

Correspondence to: Jilly F. Evans⁴ Correspondence and requests for materials should be addressed to J.F.E. (e-mail: Email: jilly_evans@merck.com).DNA and amino-acid sequences have been deposited in the GenBank/EMBL/DDBJ databases under accession number AF119711.

Abstract

The cysteinyl leukotrienes—leukotriene C₄(LTC₄), leukotriene D₄(LTD₄) and leukotriene E₄(LTE ₄)—are important mediators of human bronchial asthma^{1, 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 CysLT ₁-receptor mRNA was confined to smooth muscle cells and tissue macrophages. Finally, we mapped the human CysLT₁-receptor gene to the X chromosome.