The CysLT receptor is highly expressed

The CysLT1 receptor is highly expressed in the lung, which may be relevant for its implication in pulmonary diseases like asthma. In fact, specific antagonists of the CysLT1 receptor (pranlukast, montelukast and zafirlukast) are used in the clinic to control bronchoconstriction and inflammation in miniprep australia and allergic rhinitis [12]. In the midst of an inflammatory environment, CysLT1 receptor expression is up-regulated by many cytokines, including the Th2 cytokines IL-4 and IL-13 in monocytes and macrophages, IL-5 in eosinophils, IL-1β in HUVEC, TGFβ, IFN-γ and IL-13 in pulmonary smooth muscle cells [7], [13], [14], [15], [16], [17], [18], [19]. As a GPCR, the CysLT1 receptor is coupled to the G-proteins Gαi and Gαq [20], [21]. Through different pathways, including MAPKinases and NF-κB, it induces the transcription of several genes implicated in inflammation, such as IL-8, MCP-1, IL-4, TGFβ, P-selectin, CXC chemokine ligand 2 and NO synthase [22], [23], [24], [25], [26], [27]. Polymorphisms in the CysLT1 receptor have been identified which are associated with atopy, an important risk factor for asthma. In the English and Spanish populations, the variant T927C, due to a synonymous mutation in the CysLT1 receptor gene was associated to atopy [28]. Atopy is a genetic predisposition to develop allergies, characterized by an elevation of IgE, and is often associated with the production of inflammatory mediators such as cysLTs [29]. In addition, a serine substitution in the amino acid structure of the CysLT1 receptor resulted in the variants CysLT1-G300S and CysLT1-I206S, the only identified variants of CysLT1 due to exonic mis-sense mutations. Those have been discovered and studied in the genetically isolated population of Tristan Da Cunha, which has a high prevalence of atopy and asthma. The receptor variant CysLT1-G300S has been significantly associated with atopy whereas the polymorphism CysLT1-I206S was not associated with atopy, in this population [30], [31]. We hypothesized that the atopic phenotype may be partially influenced by an altered binding and/or signalling due to the amino-acid substitution in the receptor protein. The principal aim of this study was to investigate the signalling mechanisms of the variants CysLT1-G300S and CysLT1-I206S induced by their natural ligands, LTD4 and LTC4, in comparison with the CysLT1-WT receptor.
Materials and methods
Results
Discussion In the present work, we have shown that the natural variants CysLT1-G300S and CysLT1-I206S respond differently to cysLTs in comparison to the WT receptor. Although the cell surface expression of the receptors is equivalent, the production of IPs, phosphorylation of Erk, as well as IL-8 and IL-13 promoter transactivation are higher in the cells expressing the variant CysLT1-G300S. In addition, the binding of LTD4 appears to be higher as well. In contrast, when the cells express the variant CysLT1-I206S, their responses to cysLTs tend to be lower or similar to those of the WT receptor.