Cysteinyl leukotriene receptors, old and new; implications for asthma
The cysteinyl leukotrienes (cys-LTs) are three structurally similar, but functionally distinct lipid mediators of inflammation. The parent cys-LT, LTC4, is synthesized by and released from mast cells, eosinophils, basophils, and macrophages, and is converted to the potent constrictor LTD4 and the stable metabolite, LTE4. While only two cys-LT-selective receptors (CysLTRs) have been identified, cloned, and characterized, studies dating back three decades predicted the existence of at least three functional CysLTRs, each with a characteristic physiological function in airways and other tissues. The recent demonstration that mice lacking both known CysLTRs exhibit full (and in some instances, augmented) physiological responses to cys-LTs verifies the existence of unidentified CysLTRs. Moreover, the ability to manipulate receptor expression in both whole animal and cellular systems reveals that the functions of CysLTRs are controlled at multiple levels, including receptor-receptor interactions. Finally, studies in transgenic mice have uncovered a potentially major role for cys-LTs in controlling the induction of Th2 responses to common allergens. This review focuses on these recent findings and their potential clinical implications.