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Vol. 58, Issue 6, 1601-1608, December 2000
Departments of Pharmacology (H.P.N., Z.W., Y.Z., R.K.R., S.H.S.L.,
O.C.) and Developmental and Cell Biology (O.C.), University of
California at Irvine, Irvine, California; and NeoGene Technologies,
Inc., Irvine, CA (H.P.N., Z.W., R.K.R., O.C.)
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 = 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.
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