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Vol. 56, Issue 3, 657-663, September 1999
Departments of Pulmonary Pharmacology, Molecular Biology, Gene
Expression Sciences, Molecular Screening, Genetic Technologies, Renal
Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia,
Pennsylvania; and New Frontiers Science Park, Harlow, Essex, England
The cysteinyl leukotrienes (CysLTs) have been implicated in
the pathophysiology of inflammatory disorders, in particular
asthma, for which the CysLT receptor antagonists pranlukast,
zafirlukast, and montelukast, have been introduced recently as novel
therapeutics. Here we report on the molecular cloning, expression,
localization, and pharmacological characterization of a CysLT receptor
(CysLTR), which was identified by ligand fishing of orphan
seven-transmembrane-spanning, G protein-coupled receptors. This
receptor, expressed in human embryonic kidney (HEK)-293 cells
responded selectively to the individual CysLTs, LTC4,
LTD4, or LTE4, with a calcium mobilization response; the rank order potency was LTD4
(EC50 = 2.5 nM) > LTC4 (EC50 = 24 nM) > LTE4
(EC50 = 240 nM). Evidence was provided that LTE4 is a partial agonist at this receptor.
[3H]LTD4 binding and LTD4-induced
calcium mobilization in HEK-293 cells expressing the CysLT
receptor were potently inhibited by the structurally distinct
CysLTR antagonists pranlukast, montelukast, zafirlukast, and
pobilukast; the rank order potency was pranlukast = zafirlukast > montelukast > pobilukast.
LTD4-induced calcium mobilization in HEK-293 cells
expressing the CysLT receptor was not affected by pertussis toxin, and
the signal appears to be the result of the release from intracellular
stores. Localization studies indicate the expression of this receptor
in several tissues, including human lung, human bronchus, and human
peripheral blood leukocytes. The discovery of this receptor, which has
characteristics of the purported CysLT1 receptor subtype,
should assist in the elucidation of the pathophysiological roles of the
CysLTs and in the identification of additional receptor subtypes.
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