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 obstructi on in asthma. Pharmacological studies have suggested the existence of at le ast two types of CysLT receptors, designated CysLT(1) and CysLT(2). The Cys LT(1) receptor has been cloned recently. Here we report the molecular cloni ng, expression, localization, and functional characterization of a human G protein-coupled receptor that has the expected characteristics of a CysLT(2 ) receptor. This new receptor is selectively activated by nanomolar concent rations of CysLTs with a rank order potency of LTC4 = LTD4 >> LTE4. The leu kotriene analog BAY u9773, reported to be a dual CysLT(1)/CysLT(2) antagoni st, was found to be an antagonist at CysLT(1) sites but acted as a partial agonist at this new receptor. The structurally different CysLT(1) receptor- selective antagonists zafirlukast, montelukast, and MK-571 did not inhibit the agonist-mediated calcium mobilization of CysLT(2) receptors at physiolo gical concentrations. Localization studies indicate highest expression of C ysLT(2) receptors in adrenal glands, heart, and placenta; moderate levels i n spleen, peripheral blood leukocytes, and lymph nodes; and low levels in t he central nervous system and pituitary. The human CysLT(2) receptor gene i s located on chromosome 13q14.12-21.1. The new receptor exhibits all charac teristics of the thus far poorly defined CysLT(2) receptor. Moreover, we ha ve identified BAY u9773 as a CysLT(2) selective agonist, which could prove to be of immediate use in understanding the functional roles of the CysLT(2 ) receptor.