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Cysteinyl-leukotrienes (cysteinyl-LTs), that is, LTC4, LTD4, and LTE4, trigger contractile and inflammatory responses through the specific interaction with G protein-coupled receptors (GPCRs) belonging to the purine receptor cluster of the rhodopsin family, and identified as CysLT receptors (CysLTRs). Cysteinyl-LTs have a clear role in pathophysiological conditions such as asthma and allergic rhinitis (AR), and have been implicated in other inflammatory conditions including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. Molecular cloning of human CysLT1R and CysLT2R subtypes has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Interestingly, recent data provide evidence for the immunomodulation of CysLTR expression, the existence of additional receptor subtypes, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Furthermore, genetic variants have been identified for the CysLTRs that may interact to confer risk for atopy. Finally, a crosstalk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize and attempt to integrate recent data derived from studies on the molecular pharmacology and pharmacogenetics of CysLTRs, and will consider the therapeutic opportunities arising from the new roles suggested for cysteinyl-LTs and their receptors.

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The release kinetics of histamine and leukotrienes C4 (LTC4) and B4 (LTB4) were investigated in nasal secretions of 10 patients with hay fever after antigen challenge. High levels of biologically active histamine were found in nasal washes from asymptomatic allergic and normal subjects. With repeated lavages, the amount of histamine recovered dropped markedly. Grass pollen challenge was followed by a significant (p less than 0.05) dose-dependent and time-limited (5 min) increase in histamine level in 7 of 10 patients; these values, however, were lower than those found in basal conditions. In 8 of 10 patients with hay fever, antigen challenge induced a significant (p less than 0.05) dose-dependent increase in LTC4 level, which persisted for 30 min. The LTC4 generation was well correlated with the appearance of allergic symptoms; LTB4 production was found in 2 patients only. A different pattern of symptoms was observed after in vivo nasal stimulation with histamine and LTC4. Histamine caused sneezing, itching, rhinorrhea, and nasal obstruction; conversely, the main symptom induced by LTC4 was a more pronounced and longer lasting nasal obstruction.

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