The quest for new cysteinyl-leukotriene and lipoxin receptors: recent clues

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Abstract

The metabolism of arachidonic acid via the 5-lipoxygenase enzymatic pathway leads to the formation of the cysteinyl-leukotrienes and lipoxins, which have been implicated in several inflammatory reactions. While these lipid mediators are responsible for a variety of effects, their actions occur through the activation of 3 specific types of cloned receptors (i.e., CysLT1, CysLT2, and ALX). Although receptor activation can explain several biological actions associated with the mediators, there is some evidence to suggest that not all responses fit the well-known characteristics of these cloned receptors. Other receptor subtypes may also exist. Interestingly, the indirect evidence for support of this observation is principally derived from work performed on either blood elements and/or vascular smooth muscle. Because the initiating events associated with inflammation are essentially of vascular origin, further work at the molecular level may be necessary to confirm the data, which do not fit the well-known CysLT and ALX receptor profiles.

Introduction

The classical features of inflammatory reactions are (a) an increase in blood flow, (b) an increase in vascular permeability with migration of cells into the tissue compartment, and (c) the release of factors at the tissue sites. However, there is another aspect of the inflammatory reaction, which is frequently overlooked [i.e., (d) the resolution phase]. The latter is responsible for those interactions that provoke a return to normal physiological function. These events are associated with a variety of mediators, which activate specific receptors.

The cysteinyl-leukotrienes (cys-LTs) and the lipoxins (LXs) are lipid mediators derived from the ubiquitous membrane component arachidonic acid. The former metabolites of arachidonic acid are derived from the 5-lipoxygenase (5-LO) enzyme pathway, whereas LXs are dependent on the activity of the 5-LO pathway in collaboration with the 12-lipoxygenase and/or 15-lipoxygenase enzymatic pathways (Fig. 1). LX formation also occurs using leukotriene A4 (LTA4) as the substrate.

There is now considerable amount of evidence to suggest that the 5-LO pathway and 5-LO activating protein (FLAP) play pivotal roles in the formation of metabolites that are intimately connected with many aspects of the inflammatory process. This notion has received pertinent support from genetic investigations involving subjects with either asthma Koshino et al., 1998, Koshino et al., 1999, Choi et al., 2004 or cardiovascular inflammation (Dwyer et al., 2004). Recently, Helgadottir et al. (2004) demonstrated that an overactive version of the gene (ALOX5AP) coding for FLAP was associated with an elevated risk of myocardial infarction and stroke. These investigators also showed that cells derived from those subjects released greater amounts of a 5-LO metabolite. The data further implicate the metabolites of the 5-LO pathway in chronic cardiovascular disease.

Both cys-LTs and LXs induce their biological actions via stereoselective membrane-bound G-protein-coupled receptors (GPCRs). Eicosanoid receptors have now been phylogenically classified, and a nomenclature has been suggested Coleman et al., 1994, Brink et al., 2003, Brink et al., 2004. In addition, several elegant genetic and biochemical studies have been performed to elucidate the receptor amino acid sequences and the G-protein-dependent and -independent pathways associated with these 7-transmembrane receptors.

The aim of this presentation is to highlight the pharmacological evidence, which suggests that other endogenous CysLT and ALX receptor subtypes may exist. While this database does not directly establish the existence of receptor subtypes, the observations may provide pertinent information for further work at the molecular level.

Section snippets

Background

The concept that the myriad of actions induced by cys-LTs and LXs were via receptors was initially based on findings derived from ligand potency ratios in both functional and radioligand binding assays. The development of specific and potent CysLT antagonists further facilitated the identification and classification of the CysLT receptors into 2 main groups Drazen et al., 1980, Fleisch et al., 1982, Krell et al., 1983. The CysLT1 receptor class was based on the ability of several antagonists

Ligand selectivity at CysLT receptors

Information concerning both CysLT1 and CysLT2 receptors has been based on isolated cells transfected with cDNA for each of these receptors. The assumption was that an evaluation of the ligand-receptor interaction under well-controlled conditions (i.e., a single receptor associated with a specific effect) would facilitate an exploration of the mechanisms involved in the functional response. However, the use of tissue preparations with a single receptor had also been the basis of previous

Lipoxin receptor (ALX)

The LXs generated in mammalian systems are LXA4 and LXB4. These native ligands generally display a profile of inhibitory actions associated with the resolution phase of the inflammatory response Serhan, 1994, Levy et al., 2001. This is characterized by their ability to inhibit chemotaxis of PMN and eosinophils Samuelsson et al., 1987, Lee et al., 1989, to modulate cellular adhesion to endothelial cells (Papayianni et al., 1996), and to inhibit PMN transmigration (Colgan et al., 1993), which is

Summary

Metabolites of the 5-LO pathway have been intimately linked with various phases of inflammation. An attempt has been made in this presentation to highlight some recent evidence, which suggests the existence of other CysLT receptor subtypes (Fig. 2). The CysLT1 receptor is activated by the cys-LTs and blocked by the classical CysLT1 antagonists (high affinity receptor) and LTE4. A CysLT2 receptor is also activated by these ligands and blocked by either the nonselective CysLT1/CysLT2 antagonist

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