Introduction

The endogenous ligands for the leukotriene, lipoxin and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes, as depicted in Fig 1 [1,4]. The formation of leukotrienes by 5-lipoxygenase from acid arachidonic acid starts with the epoxide intermediate LTA₄, which serves as precursor for leukotriene synthesis (Fig. 1). Subsequent metabolism through the enzyme LTA₄ hydrolase leads to the formation of LTB₄, which is the ligand for the BLT receptors. Alternatively, the conjugation of LTA₄ with glutathione yields the cysteinyl-leukotrienes (Fig 1) acting on CysLT receptors (Fig 1). The leukotriene receptor class also includes receptors for other mediators derived from arachidonic acid through lipoxygenase metabolism, namely the ALX/FPR2 receptor for lipoxin A₄ [10], and the OXE receptor for 5-Oxo-ETE [2], as indicated in Fig 1.

BLT receptors

The dihydroxy-leukotriene, leukotriene B4 (LTB₄) stimulates neutrophil chemotaxis and secretion but may also affect immunomodulation through the activation of several leukocyte populations [1,4]. In addition, receptors for LTB₄ are expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells [3]. Chemotaxis, the principal effects of LTB₄ and related dihydroxy-acids on leukocytes, occurs via activation of BLT₁ receptors [58]. The human BLT₁ receptor is the high affinity LTB₄ receptor, consisting of 352 amino acids and encoded by a gene located on chromosome 14q11.2-q12 [58]. Transgenic overexpression of the human BLT₁ receptor in mice increased the inflammatory response to LTB₄ [9], whereas genetic BLT₁ receptor disruption decreased leukocyte chemotaxis, and protected against disease development in several different animal models [1,4]. Although the LTB₄-induced interaction with the BLT₁ receptor corresponded with several effects observed in those target cells, initial studies had revealed both high and lower affinity binding sites for LTB₄ specifically in human granulocytes. The molecular explanation for the latter finding was provided in 2000, when a gene with high sequence similarity to BLT₁ receptor was identified, and encoded a low affinity LTB₄ receptor which has subsequently been denoted BLT₂ [1,4,60]. Although LTB₄ appears to be the sole full agonist for the BLT₁ receptor, several lipoxygenase-products in addition to LTB₄ have been identified as ligands for the human BLT₂ receptor. These include 12(S)-HETE, 12(S)-HpETE, and 15(S)-HETE [59]. Furthermore, the thromboxane synthase product 12-HHT formed in activated blood platelets and macrophages from prostaglandin H2, is also a natural ligand for the BLT₂ receptor [39].

The inflammatory LTB₄ signaling through the BLT₁ and BLT₂ receptors has been implicated in several disease, such as for example bronchial asthma [55], rheumatoid arthritis [27,51], atherosclerosis [3,5], abdominal aortic aneurysms [23], bone metabolism [22], multiple sclerosis [26], and cancer [61].

CysLT receptors

The cysteinyl-leukotrienes (LTC₄, LTD₄ and LTE₄; cys-LTs) are known to be potent smooth muscle contractile agents [14]. However, these mediators have also been reported to cause plasma exudation [12], recruit eosinophils, provoke cardiodepression, induce cell proliferation and increase mucous production. Over the years, a large number of selective antagonists for CysLT receptors have been developed. These antagonists allowed to initially define the two broad subgroups of CysLT receptors, those that were blocked by these antagonists (CysLT₁) and those that were resistant to blockade (CysLT₂) [28].

The CysLT₁ and CysLT₂ receptors and are glycosylated G-protein coupled receptors with 337 and 346 amino acids, respectively [21,30]. The CysLT₁ receptor is expressed in many human tissues including lung, peripheral blood leukocytes, spleen and placenta [1,4]. Despite some overlapping with the CysLT₁ receptor, the CysLT₂ receptor exhibits a distinctive expression pattern in for example the heart, brain, and adrenal glands [4,7]. In cells transfected with the CysLT₁ recombinant receptor, LTD₄ was demonstrated to be more potent than LTC₄ and LTE₄ [1,4]. In contrast, when similar experiments were performed with the CysLT₂ recombinant receptor the agonist rank order potency was LTD₄=LTC₄ with LTE₄ less potent [1,4]. The classical CysLT₁ antagonists blocked the cysteinyl-leukotriene-induced calcium mobilization in the CysLT1 receptor transfected cells whereas in cells transfected with the CysLT₂ receptor, the ligand activation of calcium mobilization was not blocked by these antagonists. Furthermore, the BAY u9773 compound was shown to be a CysLT₂ subtype selective agonist for calcium mobilization in transfected cells [1,4]. Although CysLT receptor signaling originate from plasma membrane expression, recent studies have also demonstrated a nuclear/perinuclear expression of CysLT₁ receptors in different cell types [15,34,36].

Cysteinyl-leukotriene signaling through the CysLT₁ receptor has been mainly explored in bronchial asthma and allergic rhinitis, for which CysLT₁ receptor antagonist are presently used clinically [45]. In addition, observational studies have suggested beneficial effects of this class of drugs for the prevention of myocardial infarction and stroke [24], and experimental studies have shown a role in aortic valve stenosis [34]. The abundant expression of the CysLT₂ receptor in endothelial cells of some vascular beds, has also been implied in myocardial damage induced by ischemia/reperfusion [35]. A role for CysLT₁ and CysLT₂ activation in various cancers has also been demonstrated [4].

There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies [6,29,48,52,56], radioligand binding [8,46-47] and in mice lacking both CysLT₁ and CysLT₂ receptors [32].

LTE₄ has been suggested to signal through P2Y₁₂ receptors in some studies [19,37,40], although not consequently replicated in all settings [18]. In support of common purinergic and leukotriene signaling, the orphan GPR17 (Fig 1) has been postulated to be activated by both cysteinyl-leukotrienes and nucleotides [11], and to function as a negative regulator for LTD₄-induced CysLT₁ receptor mediated responses [31]. The formal pairing of GPR17 as a dual receptor for cysteinyl-leukotrienes and nucleotides is yet to be agreed [13].

Recent evidence point to yet another receptor for cysteinyl-leukotrienes, namely GPR99 [25] (Fig 1), which was initially recognized as the oxoglutarate receptor (OXGR1) based on its binding of 2-oxoglutarate (α-ketoglutarate) [13]. Cells transfected with the human GPR99 exhibit both functional and binding responses to LTE₄, and GPR99 deletion in mice abrogates LTE₄-induced vascular leakage [25]. Further investigations are presently necessary to distinguish the preferred endogenous ligands for GPR99.

ALX/FPR2 receptor

The dual lipoxygenation of arachidonic acid by either the 15- and 5-lipoxygenase or the 5- and 12-lipoxygenase produced eicosanoids known as lipoxins, as indicated in Fig 1 [10]. Lipoxins are inhibitory or anti-inflammatory mediators which act as a "stop signal" during inflammatory reactions [7,49]. At the molecular level the lipoxin receptor was the first recognized non-prostanoid eicosanoid G-protein coupled receptor [16-17]. This receptor is composed of 351 amino acids and the gene located to the X chromosome (19q13.3). Abundant receptor expressed is found in the lung, peripheral blood leukocytes, spleen, and lesser amounts in the heart, placenta and liver [10]. Since this receptor had high sequence homology (70%) to the formyl peptide receptor (FPR), it was initially designated as formyl peptide like receptor-1 (FPRL-1). However, although a number of peptides activate the receptor, LXA₄ is the most potent native endogenous ligand. Therefore the nomenclature recommended for this receptor is FPR2/ALX, and ALX/FPR2 when the lipoxin-binding property is of primary concern [57].

OXE receptor

Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that have been intimately associated with cellular migration [2]. 5-Oxo-ETE is formed by the oxidation of 5S-HETE by 5-hydroxyeicosanoid dehydrogenase, a highly selective NADP⁺-dependent enzyme (Fig 1) [44]. This mediator is a potent chemoattractant for human neutrophils, eosinophils, monocytes, and basophils [41-43].

Biological responses to 5-oxo-ETE are mediated by the OXE receptor, which is encoded by the OXER1 gene. This receptor was identified independently by three groups and was previously known as TG1019, R527 and GPCR48. Consistent with the biological activities of 5-oxo-ETE, the OXE receptor is highly expressed in human eosinophils ≈ basophils > neutrophils > macrophages [2] and is also expressed in a variety of cancer cell lines [38].

The OXE receptor has an amino acid composition of 423 and a gene localized to chromosome 2p21. The OXE receptor shares 23.2% and 25.3% identity with CysLT₁ and CysLT₂ respectively [2].

Since a major target of 5-oxo-ETE is the eosinophil, the OXE receptor could play an important role in eosinophilic disorders such as asthma and allergic rhinitis [33]. In addition, the OXE receptor could also be an important drug target in cancer, as it appears to play a role in cancer cell proliferation and its downregulation with siRNA has an antiproliferative effect [54]. The availability of OXE receptor antagonists, such as the recently reported indole derivative 5-(6-chloro-2-hexyl-1H-indol-1-yl)-5-oxo-valeric acid, will facilitate future investigations of OXE receptor signaling in different disease models [20].

Resolvin receptors

Besides the 20:4, n-6 fatty acid arachidonic acid, also omega-3 essential polyunsaturated fatty acids, such as eicosapentanoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3), are metabolized by lipoxygenases in human cells (Fig 1). For example, when metabolized by 5-lipoxygenase, EPA generates leukotrienes of the 5-series (e.g. LTB₅, see Fig 1) which are not biologically active but compete with leukotriene binding to the leukotriene receptors, suggesting that lipoxygenase metabolites of omega-3 fatty acids may act as inhibitors of inflammation [53]. Furthermore, EPA and DHA can enter into the lipoxygenase metabolism and lead to the biosynthesis of either E-series (for EPA-derived), or D-series (for DHA-derived) of Resolvins. These omega-3-derived mediators have been characterized as mediators of inflammation resolution. Although not yet formally classified as lipid mediator receptors, several lines of recent evidence point to GPR32 as the receptor for resolvin D1 and ChemR23 (or CMKLR1) as the receptor for resolvin E1 (Fig 1) [7,50]. The formal pairing of these receptors with their cognate ligands is however yet to be agreed [13].

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