Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors

The cysteinyl leukotrienes (cys-LTs) are a family of potent lipid mediators of inflammation derived from arachidonic acid. Activation of certain cell types results in the biosynthesis and export of leukotriene (LT) C-4, which then undergoes extracellular metabolism to LTD4 and LTE4. LTE4, the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT(1)R and CysLT(2)R, respectively). We had recognized a greater potency for LTE4 than LTC4 or LTD4 in constricting guinea pig trachea in vitro and comparable activity in eliciting a cutaneous wheal and flare response in humans. Thus, we hypothesized that a vascular permeability response to LTE4 in mice lacking both the CysLT(1)R and CysLT(2)R could establish the existence of a separate LTE4 receptor. We now report that the intradermal injection of LTE4 into the ear of mice deficient in both CysLT(1)R and CysLT(2)R elicits a vascular leak that exceeds the response to intradermal injection of LTC4 or LTD4, and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE4 is approximate to 64-fold more potent in the CysLT(1)R/CysLT(2)R double-deficient mice than in sufficient mice. The administration of a CysLT,R antagonist augmented the permeability response of the CysLT(1)R/CysLT(2)R double-deficient mice to LTC4, LTD4, and LTE4. Our findings establish the existence of a third receptor, CysLT(E)R, that responds preferentially to LTE4, the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.