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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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The leukotriene receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [6-7]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB4 receptor also binds several other lipoxygenase-products, such as 12S-HETE, 12S-HPETE, 15S-HETE, and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid. The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [41] and the vanilloid TRPV1 ligand-gated nonselective cation channel [46]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [32,47] and has recently been extended to the cryo-electron microscopy structure of LTB4-bound human BLT1 receptor at 2.91 Å resolution [73]. The receptors for the cysteinyl-leukotrienes (i.e. LTC4, LTD4 and LTE4) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. Quite recently, the the crystal structures of both receptors have been solved, the CysLT1 in complex with zafirlukast and pranlukast [42] and the CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [28]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [7]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [21,49,54], GPR17 [14] and GPR99 [37].
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OXE receptor C Show summary »« Hide summary More detailed page
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* Key recommended reading is highlighted with an asterisk
* Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Nicosia S, Serhan CN, Shimizu T, Yokomizo T. (2003) International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors. Pharmacol Rev, 55 (1): 195-227. [PMID:12615958]
* Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Rovati GE, Serhan CN, Shimizu T, Yokomizo T. (2004) International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor. Pharmacol Rev, 56 (1): 149-57. [PMID:15001665]
* Bäck M, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE. (2011) International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev, 63 (3): 539-84. [PMID:21771892]
* Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE. (2014) Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. Br J Pharmacol, 171 (15): 3551-74. [PMID:24588652]
Kanaoka Y, Boyce JA. (2004) Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J Immunol, 173 (3): 1503-10. [PMID:15265876]
* Laidlaw TM, Boyce JA. (2012) Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin Exp Allergy, 42 (9): 1313-20. [PMID:22925317]
Nelson JW, Leigh NJ, Mellas RE, McCall AD, Aguirre A, Baker OJ. (2014) ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands. Am J Physiol, Cell Physiol, 306 (2): C178-85. [PMID:24259417]
Sasaki F, Yokomizo T. (2019) The leukotriene receptors as therapeutic targets of inflammatory diseases. Int Immunol, 31 (9): 607-615. [PMID:31135881]
Serhan CN. (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature, 510 (7503): 92-101. [PMID:24899309]
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Subcommittee members:
Magnus Bäck (Chairperson)
Sven-Erik Dahlén
Jeffrey Drazen
Jilly F. Evans
G. Enrico Rovati
Takao Shimizu
Charles N. Serhan
Takehiko Yokomizo |
Other contributors:
Charles Brink
Nan Chiang
Gordon Dent
Douglas W. P. Hay
Motonao Nakamura
William Powell
Joshua Rokach
Mohib Uddin |
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Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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The FPR2/ALX receptor (nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene and Lipoxin Receptors [7]) is activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A4 (LXA4) and 15-epi-LXA4 (aspirin triggered lipoxin A4, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [13] as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides [16,56]. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor [61]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [67,69]. FPR2/ALX has also been reported to be activated by resolvin D1 [48]. The agonist activity of the lipid mediators described has been questioned [29,57], which may derive from batch-to-batch differences, partial agonism or biased agonism. Results from Cooray et al. (2013) [16] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. ATL-induced conformational changes of recombinant human ALX was demonstrated using FRET analysis [24]; ATL gives a bell-shaped concentration-response relationship, inducing maximal conformational changes of ALX at 0.1-1 nM. In addition, the crystal structure of ALX was reported at 2.8 Å resolution [12]. A receptor selective for LXB4 has been suggested from functional studies [1,45,62]. Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages.
Oxoeicosanoid receptors (OXE, nomenclature agreed by the NC-IUPHAR subcommittee on Leukotriene receptors [5]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as docosahexaenoic acid and EPA, acted as receptor antagonists [33].