Molecular and functional aspects of human cysteinyl leukotriene receptors

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Abstract

The cysteinyl leukotrienes (cys-LTs), i.e. LTC4, LTD4 and LTE4, trigger contractile and inflammatory processes through the specific interaction with cell surface receptors belonging to the purine receptor cluster of the rhodopsin family of the G protein-coupled receptor (GPCR) genes. Cys-LTs have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in a number of inflammatory conditions including cardiovascular and gastrointestinal diseases. Pharmacological studies have identified two classes of cys-LT receptors (CysLT1 and CysLT2) based on their sensitivity to CysLT1 selective antagonists, albeit there is evidence for additional subtypes. Molecular cloning of the human CysLT1 and CysLT2 receptors has confirmed both their structure as putative seven transmembrane domain G protein-coupled receptors and most of the previous pharmacological characterization. The rank order of potency of agonist activation for the CysLT1 receptor is LTD4>LTC4>LTE4 and for the CysLT2 receptor is LTC4=LTD4>LTE4. The CysLT1 receptor is most highly expressed in spleen, peripheral blood leukocytes, interstitial lung macrophages and in airway smooth muscle. The CysLT2 receptor is mostly expressed in heart, adrenals, placenta, spleen, peripheral blood leukocytes and less strongly in the brain. Gene cloning of CysLT1 and CysLT2 receptors has renewed the attention on the cys-LTs field and will, hopefully, encourage future studies on the regulation of CysLT receptors expression and the dissection of their signalling pathways. Furthermore, the peculiar pattern of expression of the two receptor subtypes will promote the discovery of new functions for cys-LTs in physiological and pathological conditions. Only CysLT1 selective receptor antagonists have been described to date and are currently available for the treatment of asthma. Molecular cloning of different CysLT receptor subtypes will certainly foster the development of new selective antagonists based on molecular modelling studies.

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].

Section snippets

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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      CysLTs and LTB4 mediates their biological activity through G protein-coupled receptors (GPCR) i.e. cysLT receptors (cysLT-1 and cysLT-2) and BLT receptors (BLT1 and BLT2) respectively (Ghosh et al., 2016). The cysLTs are characterized by the presence of a cysteine ring whereas LTB4 is a non-cysteine containing dihydroxy-leukotriene (Capra, 2004). The biological properties of leukotrienes suggest that cysLTs in particular, play an important role in the pathogenesis of allergic and severe asthma (Capra et al., 2007).

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