CysLT receptors

Nomenclature BUT, receptor CysLT, receptor (LTD4 receptor) CysLT2 receptor (LTC4 receptor)... 

These receptors share several common features, some of which are illustrated in our example, the cysteinyl leukotriene 2 (CysLT ) receptor (see Fig. 6.1) (11). These features include (1) insertion into the membrane and targeting to the plasma membrane of the cell (2) the presence of seven conserved transmembrane domains (3) three extracellular and three intracellular loops (4) an extracellular amino terminus and (5) an intracellular carboxyl terminus (1,2). 

Fig. 6.1 Schematic representation of the cysteinyl leukotriene 2 (CysLT ) receptor. Ribbon model of this family A G protein-coupled receptor (GPCR) is pictured in its heptahelical configuration. The extracellular amino terminus of the receptor, the transmembrane domains, and the intracellular carboxyl tail extend behind the intracellular palmitoylation site. The putative binding pocket for cysteinyl leukotriene ligands is derived from a rhodopsin model...

Fig. 8.2 Alignment of the protein structure of the cysteinyl leukotriene 1 (CysLTj) and 2 (CysLT ) receptors in relation to rhodopsin. The amino acids conserved between these family A receptors are shown. The consensus is greater than 50%. These data formed the basis of the model predicting the CysLTj and CysLT transmembrane domains (helices 1-7), the four [3-sheets, and the putative cysteinyl leukotiiene-binding domain. The amino acid variants that are associated with atopy or asthma, the G300S CysLTj variant, and the M201V CysLT variant are each boxed and noted with arrows...

CysLTs) are proinflammatory molecules synthesized primarily by basophils, neutrophils, and mast cells and are potent mediators of airway inflammation and bronchoconstriction (77,78). There are two classifications of drugs in this category that can regulate the effects of CysLTs inhibitors of the 5-lipoxygenase enzyme, such as zileuton, and CysLT receptor antagonists, such as montelukast and zafirlukast. 

Zafirlukast and montelukast are well tolerated. Zafirlukast increases plasma concentrations of warfarin and decreases the concentrations of theophylline and erythromycin. In rare cases, treatment of patients with CysLT receptor antagonists is associated with the development of Churg-Strauss syndrome, a condition marked by acute vasculitis, eosinophilia, and a worsening of pulmonary symptoms. Because these symptoms often appear when patients are given the leukotriene receptor antagonists when they are being weaned from oral corticosteroid therapy, it is not clear whether they are related to the action of the antagonists or are due to a sudden reduction in corticosteroid therapy. 

Leukotriene Antagonists. The leukotrienes are metabolites of arachidonic acid generated de novo after inflammatory cell activation [69,75] and are potent bronchoconstrictors and proinflammatory agents (vide supra). The biological effects of the cysteinyl-leukotrienes (viz. C4, D4, and E4) and of leukotriene B4 are mediated via cysLTi and BLT receptors, respectively [69,76]. The development of potent, selective cysLT receptor antagonists, such as montelukast, pranlukast,... 

Montelukast inhibits the actions of leukotriene D4 (LTD4) at the CysLT, receptor. This results in a decrease in sensitivity to antigen challenge, and decreased bronchoconstriction. 

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