Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist.

The cysteinyl leukotrienes (CysLTs) are potent biological mediators in the pathophysiology of inflammatory diseases, in particular of airway obstruction in asthma. Pharmacological studies have suggested the existence of at least two types of CysLT receptors, designated CysLT1 and CysLT2. The CysLT1 receptor has been cloned recently. Here we report the molecular cloning, expression, localization, and functional characterization of a human G protein-coupled receptor that has the expected characteristics of a CysLT2 receptor. This new receptor is selectively activated by nanomolar concentrations of CysLTs with a rank order potency of LTC4 5 LTD4 . . LTE4. The leukotriene analog BAY u9773, reported to be a dual CysLT1/ CysLT2 antagonist, was found to be an antagonist at CysLT1 sites but acted as a partial agonist at this new receptor. The structurally different CysLT1 receptor-selective antagonists zafirlukast, montelukast, and MK-571 did not inhibit the agonist-mediated calcium mobilization of CysLT2 receptors at physiological concentrations. Localization studies indicate highest expression of CysLT2 receptors in adrenal glands, heart, and placenta; moderate levels in spleen, peripheral blood leukocytes, and lymph nodes; and low levels in the central nervous system and pituitary. The human CysLT2 receptor gene is located on chromosome 13q14.12‐21.1. The new receptor exhibits all characteristics of the thus far poorly defined CysLT2 receptor. Moreover, we have identified BAY u9773 as a CysLT2 selective agonist, which could prove to be of immediate use in understanding the functional roles of the CysLT2 receptor.