Cysteinyl leukotriene receptor 2
Cysteinyl leukotriene receptor 2, also termed CYSLTR2, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR2, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) contributes to mediating various allergic and hypersensitivity reactions in humans. However, the first discovered receptor for these CsLTs, cysteinyl leukotriene receptor 1 (CysLTR1), appears to play the major role in mediating these reactions.
The human CysLTR2 gene maps to the long arm of chromosome 13 at position 13q14, a chromosomal region that has long been linked to asthma and other allergic diseases. The gene consists of four exons with all introns located in the genes' 5' UTR region and the entire coding region located in the last exon. 'CysLTR2 encodes a protein composed of 347 amino acids and shows only modest similarity to the CysLTR1 gene in that its protein shares only 31% amino acid identity with the CysLTR1 protein.
CySLTR2 mRNA is co-expressed along with CysLRR1 in human blood eosinophils and platelets, and tissue mast cells, macrophages, airway epithelial cells, and vascular endothelial cells. It is also expressed without CysLTR1 throughout the heart, including Purkinje cells, adrenal gland, and brain as well as some vascular endothelial, airway epithelial, and smooth muscle cells.
CysLTR2, similar to CysLTR1, is a G protein–coupled receptor that links to and when bound to its CysLT ligands activates the Gq alpha subunit and/or Ga subunit of its coupled G protein, depending or the cell type. Acting through these G proteins and their subunits, ligand-bound CysLTR1 activates a series of pathways that lead to cell function (see Gq alpha subunit#function and Ga subunit#function for details); the order of potency of the cysLTs in stimulating CysLTR2 is LTD4=LTC4>LTE4 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo. By comparison, the stimulating potencies of these CysLTs for CysLTR1 is LTD4>LTC4>LTE4 with LTD4 showing 10-fold greater potency on CysLTR1 than CysLTR2. Perhaps related to this difference in CysLT sensitivities, cells co-expressing CysLTR2 and CysLTR1 may exhibit lower sensitivity to LTD4 than do cells expressing only CysLTR1; in consequence, CysLTR2 has been suggested to dampen CysLTR1's activities.
In addition to CysLTR1, GPR99 (also termed the oxoglutarate receptor or, sometimes, CysLTR3) appears to be an important receptor for CysLTs, particularly for LTE4: the CystLTs show relative potencies of LTE4>LTC4>LTD4 in stimulating GPR99-bearing cells and GPR99-deficient mice exhibit a dose-dependent loss of vascular permeability responses in skin to LTE4 but not to LTC4 or LTD4.
Other studies on model cells for allergy have defined GPR17 (also termed the uracil nucleotide/cysteinyl leukotriene receptor) as a receptor not only uracil nucleotides but also for CysLTs, with CysLTs having the following potencies LTD4>LTC4>LTE4 in stimulating GPR17-bearing cells. However, recent studies also working with model cells involved in allergy find that GPR17-bearing cells do not respond to these CysLTs (or uracil nucleotides). Rather, they find that: a) cells expressing both CysLTR1 and GPR17 receptors exhibit a marked reduction in binding and responding to LTD4 and b) mice lacking GPR17 are hyper-responsive to igE in a model for passive cutaneous anaphylaxis. The latter studies conclude that GPR17 acts to inhibit CysLTR1. Finally, and in striking contrast to these studies, repeated studies on neural tissues find that Oligodendrocyte progenitor cells express GPR17 and respond through this receptor to LTC4, LTD4, and certain purines (see GPR17#Function).
There are as yet no selective inhibitors of CysLTR2 that are in clinical use (see Clinical significance section below). However, Gemilukast (ONO-6950) reportedly inhibits both CysLTR1 and CysLTR2. The drug is currently being evaluated in phase II trials for the treatment of asthma.
Polymorphism in the CysLTR2 gene resulting in a single amino acid substitution, M201V (i.e. amino acid methionine changed for valine at the 201 position of CysLTR2 protein) has been negatively associated in Transmission disequilibrium testing with the inheritance of asthma in separate populations of: a) white and African-Americans from 359 families with a high prevalence of asthma in Denmark and Minnesota, USA, and b) 384 families with a high prevalence of asthma from the Genetics of Asthma International Network. The M201V CysLTR2 variant exhibits decreased responsiveness to LTD4 suggesting that this hypo-responsiveness underlies its asthma transmission-protecting effect. A -1220A>C (i.e. nucleotide adenine substituted for cytosine at position 1220 upstream from the transcription start site) gene polymorphism variant in intron III the upstream region of CysLTR2 has been associated significantly with development of asthma in a Japanese population; the impact of this polymorphism on the genes expression or product has not been determined. These results suggest that CYSLTR2 contributes to the etiology and development asthma and that drugs targeting CYSLTR2 may work in a manner that differs from those of CYSLTR1 antagonists.
The CysLT-induced activation of CysLTR2 induces many of the same in vitro responses of cells involved in allergic reactions as well as the in vivo allergic responses in animal models as that induced by CysLT-induced CysLTR1 (see Cysteinyl leukotriene receptor 1#Receptor. However, CysLT2 requires 10-fold higher concentrations of LTD4, the most potent cysLT for CysLTR1, to activate CysLTR2. Furthermore, the allergic and hypersensitivity responses of humans and animal models are significantly reduced by chronic treatment with Montelukast, Zafirlukast, and Pranlukast, drugs which are selective receptor antagonists of CysLTR1 but not CysLTR2. Models of allergic reactions in Cysltr2-deficient mice as well as in a human mast cell line indicate that mouse Cysltr2 and its human homolog CysLTR2 act to inhibit Cysltr1 and CysLTR1, respectively, and therefore suggest that CysLTR2 may similarly inhibit CysLTR1 in human allergic diseases. The role of CysLTR2 in the allergic and hypersensitivity diseases of humans must await the development of selective CysLTR2 inhibitors.
- GRCh38: Ensembl release 89: ENSG00000152207 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000033470 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Takasaki J, Kamohara M, Matsumoto M, Saito T, Sugimoto T, Ohishi T, Ishii H, Ota T, Nishikawa T, Kawai Y, Masuho Y, Isogai T, Suzuki Y, Sugano S, Furuichi K (August 2000). "The molecular characterization and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor". Biochem Biophys Res Commun. 274 (2): 316–22. doi:10.1006/bbrc.2000.3140. PMID 10913337.
- Van Keer C, Kersters K, De Ley J (September 1976). "L-Sorbose metabolism in Agrobacterium tumefaciens". Antonie van Leeuwenhoek. 42 (1–2): 13–24. doi:10.1007/BF00399445. PMID 1085123.
- "Entrez Gene: CYSLTR2 cysteinyl leukotriene receptor 2".
- Thompson MD, Takasaki J, Capra V, Rovati GE, Siminovitch KA, Burnham WM, Hudson TJ, Bossé Y, Cole DE (2006). "G-protein-coupled receptors and asthma endophenotypes: the cysteinyl leukotriene system in perspective". Molecular Diagnosis & Therapy. 10 (6): 353–66. doi:10.1007/bf03256212. PMID 17154652.
- Fukai H, Ogasawara Y, Migita O, Koga M, Ichikawa K, Shibasaki M, Arinami T, Noguchi E (2004). "Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma". Pharmacogenetics. 14 (10): 683–90. doi:10.1097/00008571-200410000-00006. PMID 15454733.
- Singh RK, Tandon R, Dastidar SG, Ray A (November 2013). "A review on leukotrienes and their receptors with reference to asthma". The Journal of Asthma. 50 (9): 922–31. doi:10.3109/02770903.2013.823447. PMID 23859232.
- Liu M, Yokomizo T (2015). "The role of leukotrienes in allergic diseases". Allergology International. 64 (1): 17–26. doi:10.1016/j.alit.2014.09.001. PMID 25572555.
- Zhang J, Migita O, Koga M, Shibasaki M, Arinami T, Noguchi E (June 2006). "Determination of structure and transcriptional regulation of CYSLTR1 and an association study with asthma and rhinitis". Pediatric Allergy and Immunology. 17 (4): 242–9. doi:10.1111/j.1399-3038.2005.00347.x. PMID 16771777.
- Cattaneo M (2015). "P2Y12 receptors: structure and function". Journal of Thrombosis and Haemostasis. 13 Suppl 1: S10–6. doi:10.1111/jth.12952. PMID 26149010.
- Kanaoka Y, Boyce JA (2014). "Cysteinyl leukotrienes and their receptors; emerging concepts". Allergy, Asthma & Immunology Research. 6 (4): 288–95. doi:10.4168/aair.2014.6.4.288. PMC 4077954
. PMID 24991451.
- Bankova LG, Lai J, Yoshimoto E, Boyce JA, Austen KF, Kanaoka Y, Barrett NA (May 2016). "Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99". Proceedings of the National Academy of Sciences of the United States of America. 113 (22): 6242–7. doi:10.1073/pnas.1605957113. PMC 4896673
. PMID 27185938.
- Kanaoka Y, Maekawa A, Austen KF (April 2013). "Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand". The Journal of Biological Chemistry. 288 (16): 10967–72. doi:10.1074/jbc.C113.453704. PMC 3630866
. PMID 23504326.
- Itadani S, Yashiro K, Aratani Y, Sekiguchi T, Kinoshita A, Moriguchi H, Ohta N, Takahashi S, Ishida A, Tajima Y, Hisaichi K, Ima M, Ueda J, Egashira H, Sekioka T, Kadode M, Yonetomi Y, Nakao T, Inoue A, Nomura H, Kitamine T, Fujita M, Nabe T, Yamaura Y, Matsumura N, Imagawa A, Nakayama Y, Takeuchi J, Ohmoto K (2015). "Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma". Journal of Medicinal Chemistry. 58 (15): 6093–113. doi:10.1021/acs.jmedchem.5b00741. PMID 26200813.
- Brochu-Bourque A, Véronneau S, Rola-Pleszczynski M, Stankova J (2011). "Differential signaling defects associated with the M201V polymorphism in the cysteinyl leukotriene type 2 receptor". The Journal of Pharmacology and Experimental Therapeutics. 336 (2): 431–9. doi:10.1124/jpet.110.172411. PMID 20966037.
- Haeggström JZ, Funk CD (October 2011). "Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease". Chemical Reviews. 111 (10): 5866–98. doi:10.1021/cr200246d. PMID 21936577.
- Anwar Y, Sabir JS, Qureshi MI, Saini KS (April 2014). "5-lipoxygenase: a promising drug target against inflammatory diseases-biochemical and pharmacological regulation". Current Drug Targets. 15 (4): 410–22. doi:10.2174/1389450114666131209110745. PMID 24313690.
- Kar M, Altıntoprak N, Muluk NB, Ulusoy S, Bafaqeeh SA, Cingi C (March 2016). "Antileukotrienes in adenotonsillar hypertrophy: a review of the literature". European Archives of Oto-Rhino-Laryngology. 273: 4111–4117. doi:10.1007/s00405-016-3983-8. PMID 26980339.
- Oussalah A, Mayorga C, Blanca M, Barbaud A, Nakonechna A, Cernadas J, Gotua M, Brockow K, Caubet JC, Bircher A, Atanaskovic M, Demoly P, K Tanno L, Terreehorst I, Laguna JJ, Romano A, Guéant JL (April 2016). "Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review". Allergy. 71 (4): 443–62. doi:10.1111/all.12821. PMID 26678823.
- Austen KF, Maekawa A, Kanaoka Y, Boyce JA (2009). "The leukotriene E4 puzzle: finding the missing pieces and revealing the pathobiologic implications". The Journal of Allergy and Clinical Immunology. 124 (3): 406–14; quiz 415–6. doi:10.1016/j.jaci.2009.05.046. PMC 2739263
. PMID 19647860.
- Jiang Y, Borrelli LA, Kanaoka Y, Bacskai BJ, Boyce JA (2007). "CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells". Blood. 110 (9): 3263–70. doi:10.1182/blood-2007-07-100453. PMC 2200919
. PMID 17693579.
- Nothacker HP, Wang Z, Zhu Y, et al. (2001). "Molecular cloning and characterization of a second human cysteinyl leukotriene receptor: discovery of a subtype selective agonist". Mol. Pharmacol. 58 (6): 1601–8. PMID 11093801.
- Mita H, Hasegawa M, Saito H, Akiyama K (2002). "Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils". Clin. Exp. Allergy. 31 (11): 1714–23. doi:10.1046/j.1365-2222.2001.01184.x. PMID 11696047.
- Takeda S, Kadowaki S, Haga T, et al. (2002). "Identification of G protein-coupled receptor genes from the human genome sequence". FEBS Lett. 520 (1–3): 97–101. doi:10.1016/S0014-5793(02)02775-8. PMID 12044878.
- Shirasaki H, Kanaizumi E, Watanabe K, et al. (2003). "Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa". Clin. Exp. Allergy. 32 (7): 1007–12. doi:10.1046/j.1365-2222.2002.01425.x. PMID 12100046.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241
. PMID 12477932.
- Sjöström M, Johansson AS, Schröder O, et al. (2004). "Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells". Arterioscler. Thromb. Vasc. Biol. 23 (8): e37–41. doi:10.1161/01.ATV.0000082689.46538.DF. PMID 12816881.
- Mellor EA, Frank N, Soler D, et al. (2003). "Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R". Proc. Natl. Acad. Sci. U.S.A. 100 (20): 11589–93. doi:10.1073/pnas.2034927100. PMC 208802
. PMID 13679572.
- Thompson MD, Storm van's Gravesande K, Galczenski H, et al. (2004). "A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha". Pharmacogenetics. 13 (10): 641–9. doi:10.1097/00008571-200310000-00008. PMID 14515063.
- Dunham A, Matthews LH, Burton J, et al. (2004). "The DNA sequence and analysis of human chromosome 13". Nature. 428 (6982): 522–8. doi:10.1038/nature02379. PMC 2665288
. PMID 15057823.
- Fukai H, Ogasawara Y, Migita O, et al. (2005). "Association between a polymorphism in cysteinyl leukotriene receptor 2 on chromosome 13q14 and atopic asthma". Pharmacogenetics. 14 (10): 683–90. doi:10.1097/00008571-200410000-00006. PMID 15454733.
- Pillai SG, Cousens DJ, Barnes AA, et al. (2005). "A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma". Pharmacogenetics. 14 (9): 627–33. doi:10.1097/00008571-200409000-00007. PMID 15475736.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928
. PMID 15489334.
- Hui Y, Cheng Y, Smalera I, et al. (2005). "Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure". Circulation. 110 (21): 3360–6. doi:10.1161/01.CIR.0000147775.50954.AA. PMID 15545522.
- Corrigan C, Mallett K, Ying S, et al. (2005). "Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis". J. Allergy Clin. Immunol. 115 (2): 316–22. doi:10.1016/j.jaci.2004.10.051. PMID 15696087.
- Uzonyi B, Lötzer K, Jahn S, et al. (2006). "Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells". Proc. Natl. Acad. Sci. U.S.A. 103 (16): 6326–31. doi:10.1073/pnas.0601223103. PMC 1458877
. PMID 16606835.
- Woszczek G, Chen LY, Nagineni S, et al. (2007). "IFN-gamma induces cysteinyl leukotriene receptor 2 expression and enhances the responsiveness of human endothelial cells to cysteinyl leukotrienes". J. Immunol. 178 (8): 5262–70. doi:10.4049/jimmunol.178.8.5262. PMID 17404310.
- Klotsman M, York TP, Pillai SG, et al. (2007). "Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast". Pharmacogenet. Genomics. 17 (3): 189–96. doi:10.1097/FPC.0b013e3280120043. PMID 17460547.
- "Leukotriene Receptors: CysLT2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.