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  • CysLTs trigger contractile and inflammatory processes throug

    2020-06-28

    CysLTs trigger contractile and inflammatory processes through the specific interaction with cell surface receptors belonging to the rhodopsin family of the G protein-coupled receptor (GPCR) genes. Until now, two receptor subtypes have been cloned, namely CysLT1 and CysLT2[8]. In particular, when the CysLT1 receptor is expressed in recombinant systems it shows a preferential coupling to Gq/11, whereas when constitutively expressed it has been reported to activate both pertussis toxin (PTX)-sensitive and -insensitive G-proteins [8], [9]. This was demonstrated in dimethyl sulfoxide-differentiated U937 (dU937) cells, an immortalized cell line known to constitutively express a high density of CysLT1 receptors upon differentiation to monocytes/macrophages [10], [11], CysLT1 receptors respond to LTD4 with a strong increase in cytosolic Ca2+ concentration ([Ca2+]) partially sensitive to PTX, and with the activation of the Ras-MAPK cascade totally dependent upon Gi/o[12]. These signaling effects were totally inhibited by various specific CysLT1-receptor antagonists, and no CysLT2 receptor mRNA was detected [13], [14], thus indicating that in monocyte-macrophage like U937 cells LTD4-induced responses can be totally ascribed to a CysLT1 receptor. The promonocytic leukemia cell U937 was selected because closely related to the inflammatory cells responsible of many CysLT biological actions, and because monocyte/macrophages activation leads to the release of a wide spectrum of cytokines and chemokines that have key roles in all inflammatory diseases. CysLT receptors belong to the group A subfamily of GPCRs and, in particular, to a cluster of receptors phylogenetically related to the purine P2Y receptors [15]. In addition to a number of orphan receptors this cluster includes receptors that respond to purinergic or pyrimidinergic nucleotides (P2Y receptors, see also below), proteases (F2R) and chemoattractants (FPR) [16], [17]. The CysLT receptor nomenclature was originally based on the sensitivity to the antagonists, which include montelukast, zafirlukast, pranlukast, pobilukast and MK571 [9]. Montelukast (SingulairĀ®), a potent CysLT1 receptor antagonist belonging to the chemical class of quinolines [18], is an effective and well-tolerated preventative drug for TNF-alpha, recombinant human protein and allergic rhinitis in adults and children [19]. Pranlukast (OnonĀ®, AzlaireĀ®) belongs to the chemical class of benzopyrans [20] and is indicated for the prophylactic treatment of chronic bronchial asthma in pediatric and adult patients and is currently on the market only in Japan and South America [21]. CysLT1 receptor antagonists have proven effective in various models of induced asthma, as well as in the treatment of chronic asthma. Preclinical and clinical studies have demonstrated that they differ in terms of potency and pharmacokinetics, but have similar pharmacodynamic profiles [22], [23], [24]. Conversely, P2Y receptors are GPCRs responsive to both adenine (ATP, ADP) and uracil (UTP, UDP) nucleotides, or to sugar nucleotides (UDP-glucose and UDP-galactose) [25]. Eight P2Y receptor subtypes are currently recognized: the P2Y1,2,4,6,11,12,13,14 receptors (ibidem). These receptors are widely distributed in human tissues, and important pathophysiological roles in brain function, haemostasis, regulation of blood pressure, inflammation and respiratory functions have been suggested [26]. Based on structural, phylogenetic properties TNF-alpha, recombinant human protein and signaling coupling, a subclassification of P2Y receptors into the A and B subclasses has been recently proposed. Receptors in the A subclass (P2Y1,2,4,6,11) are preferentially coupled to Gq or Gs proteins, thus mediating stimulation of phospholipase C and adenylyl cyclase. Receptors in the B subclass (P2Y12,13,14) are instead mainly linked through Gi activation to inhibition of adenylyl cyclase activity (ibidem). There are several similarities between the CysLT and the P2Y receptor classes. For example, the BLT1 receptor was originally reported as a potential nucleotide receptor based on homology with P2Y receptors but was subsequently found to be insensitive to nucleotides [27]. In a study with chimeric CysLT1/P2Y2 receptors, the chimera essentially behave as the CysLT1 receptor and the activation was antagonized by a CysLT1 receptor antagonist [28]. Crosstalk between purine and leukotriene systems has recently been reported, although the CysLT1 receptor is not a P2Y nucleotide receptor [21]. P2Y1 and CysLT receptors mediate co-release of purines and CysLTs in primary cultures of rat microglia [29].