Susan R. George

Characterization of the Human Cysteinyl Leukotriene 2 Receptor

The contractile and inflammatory actions of the cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, are thought to be mediated through at least two distinct but related CysLT G protein-coupled receptors. The human CysLT1 receptor has been recently cloned and characterized. We describe here the cloning and characterization of the second cysteinyl leukotriene receptor, CysLT2, a 346-amino acid protein with 38% amino acid identity to the CysLT1 receptor. The recombinant human CysLT2 receptor was expressed in Xenopusoocytes and HEK293T cells and shown to couple to elevation of intracellular calcium when activated by LTC4, LTD4, or LTE4. Analyses of radiolabeled LTD4 binding to the recombinant CysLT2 receptor demonstrated high affinity binding and a rank order of potency for competition of LTC4 = LTD4 ≫ LTE4. In contrast to the dual CysLT1/CysLT2 antagonist, BAY u9773, the CysLT1 receptor-selective antagonists MK-571, montelukast (SingulairTM), zafirlukast (AccolateTM), and pranlukast (OnonTM) exhibited low potency in competition for LTD4 binding and as antagonists of CysLT2receptor signaling. CysLT2 receptor mRNA was detected in lung macrophages and airway smooth muscle, cardiac Purkinje cells, adrenal medulla cells, peripheral blood leukocytes, and brain, and the receptor gene was mapped to chromosome 13q14, a region linked to atopic asthma.