Molecular and functional aspects of human cysteinyl leukotriene receptors
Introduction
Cysteinyl leukotriene (cys-LTs) receptors are seven transmembrane-spanning receptors that couple to G proteins and activate intracellular signalling pathways in response to their endogenous ligands, namely leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), collectively referred as cysteine-containing leukotrienes (cys-LTs). These have a clear role in respiratory diseases such as asthma, allergic rhinitis and other nasal allergies [1], [2], [3], [4], and have been implicated in other inflammatory conditions including cardiovascular, gastrointestinal, skin and immune disorders [5], [6]. Indeed, increased urinary excretion has been reported after episodes of unstable angina and acute myocardial infarction [7], in coronary artery disease and after coronary artery bypass surgery [8] as well as in patients with atopic dermatitis [9], rheumatoid arthritis [10], Crohn’s disease [11] or malignant astrocytoma [12], besides in patients affected by a number of respiratory diseases such as asthma [13], [14], virus-induced wheezing [15], seasonal allergic rhinitis [16] and bronchial hyperreactivity [17].
Pharmacological studies identified at least two receptors for cys-LTs [18], [19], whose characteristics were then largely confirmed by molecular biology studies that allowed the cloning of two genes for the human CysLT1 [20], [21] and CysLT2 receptors [22], [23], [24]. These belong to the rhodopsin family of the G protein-coupled receptor (GPCR) gene superfamily and, in particular, to the purine receptor cluster (within the δ group) of phylogenetically related receptors, which includes, besides a number of orphans, receptors that respond to purinergic or pyrimidinergic nucleotides (P2Ys), proteases (F2Rs) and chemoattractants (FPRs) [25], [26] (Fig. 1). Surprisingly, the receptors for the chemoattractant leukotriene B4 (BLTs) belong to the chemokine receptor cluster of the γ group, evolutionary distant from the δ group which encompasses the CysLT receptors. Unlike the monoamine or neuropeptide receptors, the receptors belonging to the purine cluster have no clear homologues in invertebrates, suggesting a relatively recent evolutionary origin [27], [28].
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Biochemical and cellular origins of cys-LTs
The study of the cys-LTs began more than 60 years ago when Feldberg and Kellaway first reported that antigen perfusion of guinea pig lung produced the release of a material they named “slow reaction smooth muscle-stimulating substance (SRS)”, which contracted the isolated guinea pig ileum [29]. Further, came the observation that this substance, renamed “slow-reacting substance of anaphylaxis or SRS-A”, was released by antigen challenge in human lungs [30]. The discovery of the precise
Classification of CysLT receptors
During the last 10 years, a committee appointed by the International Union of Pharmacology (IUPHAR) made a significant effort toward the classification and nomenclature of leukotriene receptors [53], [54], [55]. According to this nomenclature, the receptors for cys-LTs are termed CysLT. CysLT receptor nomenclature was originally based on the sensitivity to the so-called “classical” antagonists, which include montelukast (Singulair®) [56], zafirlukast (Accolate®) [57], [58], pranlukast (Onon®,
Molecular and pharmacological characterization
In spite of the considerable effort made by many research groups, CysLT receptors escaped gene cloning with conventional approaches for many years. Only in 1999, two separate groups cloned the first CysLT receptor, the hCysLT1 subtype, using bioinformatics and high throughput screening under the strategy of identifying cognate ligands for orphan GPCRs [20], [21]. The following year came the molecular cloning of the hCysLT2 receptor by three different groups [22], [23], [24].
Hydrophobicity
Localization and functional significance
The pathophysiological role of cys-LTs in asthma is well documented [2], [6], [85] and during the last 20 years a considerable effort has been made to identify and develop receptor antagonists to improve asthma management, limit its morbidity, and reduce the side effects of current medications. Localization studies were consistent with the antibronchoconstrictive and anti-inflammatory activity of CysLT1 receptor antagonists [20], [72], and the finding of CysLT receptor expression in other
Conclusions
The results obtained with recombinant hCysLT1 and hCysLT2 receptors have confirmed most of the previous findings based on classical pharmacological studies in different tissues and cells. The cloning of these receptors will prompt more detailed investigations about their signal transduction systems and the regulation of their expression in normal and disease states, but also spur the development of potent and selective CysLT2 and CysLT1/CysLT2 receptor antagonists to be used as therapeutic
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