Characterization of the human cysteinyl leukotriene CysLT1 receptor

Abstract

The cysteinyl leukotrienes-leukotriene C4(LTC4), leukotriene D4(LTD4) and leukotriene E4(LTE4)-are important mediators of human bronchial asthma. Pharmacological studies have determined that cysteinyl leukotrienes activate at least two receptors, designated CysLT1 and CysLT2. The CysLT1-selective antagonists, such as montelukast (Singulair), zafirlukast (Accolate) and pranlukast (Onon), 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 receptor. 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.

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

“…CysLT 1 can initiate signaling through the G q subunit, thereby activating PLC-␤ isoforms and inducing an increase in inositol phosphate and diacylglycerol (16,17). These secondary messengers may synergize with those triggered by TCR engagement and thus lower the threshold for Ag-specific T cell activation at sites of inflammation.…”

“…2A where cross-linking of the TCR present on the surface of CD4 ϩ T cells isolated from LatY136F mice failed to stimulate Ca 2ϩ influx. In contrast, CysLT 1 can initiate signaling through the G q subunit and thereby mediates PLC-␥1 activation and calcium mobilization (16,17). Therefore, we determined whether LatY136F CD4 ϩ T cells were capable of Ca 2ϩ mobilization in response to LTD 4 , the physiological ligand of CysLT 1 .…”

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor

“…3 Cysteinyl leukotrienes (CysLTs; leukotriene [LT] C 4 , LTD 4 , and LTE 4 ) are lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway that are involved in pathogenesis of a variety of chronic inflammatory disorders, including bronchial asthma, allergic rhinitis, pulmonary fibrosis, and atherosclerosis. 4,5 The biologic actionsof CysLTs can be mediated through3 known G protein-coupled receptors: the CysLT type 1 (CysLTR 1 ) 6 and type 2 (CysLTR 2 ) 7 receptors and the recently described receptor GPR17. 8 CysLTs have been recognized primarily as mediators involved in the development of phenotypes characteristic for bronchial asthma, such as bronchoconstriction, mucus secretion, and bronchial hyperresponsiveness.…”

Endogenous production of leukotriene D4 mediates autocrine survival and proliferation via CysLT1 receptor signalling in intestinal epithelial cells

“…Leukotriene D 4 (LTD 4 ) is the most potent of the three CysLTs (LTC 4 , LTD 4 and LTE 4 ) and its effects are mediated through either one of two G-protein-coupled receptors, CysLT 1 or CysLT 2 (Lynch et al, 1999;Heise et al, 2000;Funk, 2001). The CysLT 1 receptor (CysLT 1 R) can activate different intracellular pathways, and thus simultaneously regulate various cellular functions.…”