Characterization of the human cysteinyl leukotriene 2 receptor

The contractile and inflammatory actions of the cysteinyl leukotrienes (Cys LTs), LTC4, LTD4, and LTE4, are thought to be mediated through at least two distinct but related CysLT G protein-coupled receptors. The human CysLT(1) receptor has been recently cloned and characterized. We describe here the cloning and characterization of the second cysteinyl leukotriene receptor, CysLT(2), a 346-amino acid protein with 38% amino acid identity to the CysL T(1) receptor. The recombinant human CysLT(2) receptor was expressed in Xen opus oocytes and HEK293T cells and shown to couple to elevation of intracel lular calcium when activated by LTC4, LTD4, or LTE4. Analyses of radiolabel ed LTD4 binding to the recombinant CysLT(2) receptor demonstrated high affi nity binding and a rank order of potency for competition of LTC4 = LTD4 >> LTE4. In contrast to the dual CysLT(1)/ CysLT(2) antagonist, BAY u9773, the CysLT(1) receptor-selective antagonists MK-571, montelukast (Singulair(TM) ), zafirlukast (Accolate(TM)), and pranlukast (Onon(TM)) exhibited low pote ncy in competition for LTD4 binding and as antagonists of CysLT(2) receptor signaling. CysLT(2) receptor mRNA was detected in lung macrophages and air way smooth muscle, cardiac Purkinje cells, adrenal medulla cells, periphera l blood leukocytes, and brain, and the receptor gene was mapped to chromoso me 13q14, a region linked to atopic asthma.