Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends.
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.
Capra
Valérie
V
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. ValerieCapra@unimi.it
Thompson
Miles D
MD
Sala
Angelo
A
Cole
David E
DE
Folco
Giancarlo
G
Rovati
G Enrico
GE
D000328:Adult; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D002318:Cardiovascular Diseases / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000209:etiology; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000031:analogs & derivatives; D020024:Leukotriene Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D017997:Leukotriene C4 / Q000502:physiology*; D017998:Leukotriene D4 / Q000502:physiology*; D017999:Leukotriene E4 / Q000502:physiology*; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010597:Pharmacogenetics; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011983:Receptors, Purinergic / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D006255:Rhinitis, Allergic, Seasonal / Q000188:drug therapy / Q000503:physiopathology; D013189:SRS-A / Q000096:biosynthesis; D014018:Tissue Distribution
D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D011983:Receptors, Purinergic; D011994:Recombinant Proteins; D013189:SRS-A; C083173:leukotriene C4 receptor; C083171:leukotriene E4 receptor; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; C083169:leukotriene D4 receptor; C063449:zileuton; D006918:Hydroxyurea