Cysteinyl leukotriene receptor 1

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CYSLTR1
Identifiers
Aliases CYSLTR1, CYSLT1, CYSLT1R, CYSLTR, HMTMF81, cysteinyl leukotriene receptor 1
External IDs MGI: 1926218 HomoloGene: 4837 GeneCards: 10800
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_006639
NM_001282186
NM_001282187
NM_001282188

NM_001281859
NM_001281862
NM_021476

RefSeq (protein)

NP_001269115.1
NP_001269116.1
NP_001269117.1
NP_006630.1

NP_001268788.1
NP_001268791.1
NP_067451.2

Location (UCSC) Chr X: 78.27 – 78.33 Mb Chr X: 106.57 – 106.6 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs) contributes to mediating various allergic and hypersensitivity reactions in humans.

Gene[edit]

The human CysLTR1 gene maps to the long arm of chromosome 10 at position q21.1, contains three exons with the entire open reading frame located in exon 3, and codes for a protein composed of 337 amino acids. The CYSLTR1 gene promoter region is distanced from 665 to 30 bp upstream of its transcription start site.[3][4]

Receptor[edit]

CYSLTR1 mRNA is expressed in lung smooth muscle, lung macrophages, monocytes, eosinophils, basophils, neutrophils, T cells, B lymphocytes, pluripotent hematopoietic stem cells (CD34+), mast cells, pancreas, small intestine, prostate, interstitial cells of the nasal mucosa, airway smooth muscle cells, bronchial fibroblasts and vascular endothelial cells.[3][4]

CysLTR1 is a G protein–coupled receptor that links to and when bound to its CysLT ligand activates the Gq alpha subunit of its coupled G protein. This in turn activates a series of pathways that lead to cell function (see Gq alpha subunit#function for details); the order of potency of the cysLTs in stimulating CysLTR1 is LTD4>LTC4>LTE4[5] with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo.[4]

Other cysLT receptors include cysteinyl leukotriene receptor 2 (i.e. CysLTR2), GPR99 (also termed the oxoglutarate receptor and, sometimes, CysLTR3), and GPR17 (also termed the uracil nucleotide/cysteinyl leukotriene receptor).[4] the order of potency of the cysLTs in stimulating CysLTR2 is LTD4=LTC4>LTE4[5] with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR2 in vivo.[4] GPR99 appears to be important receptor for LTE4 in that mice lacking this receptor exhibit a dose-dependent loss of vascular permeability responses to LTE4 but not LTC4 or LTD4; the relative affinity of this receptor for CysLTs are LTE4>LTC4>LTD4.[4][6][7] GPR17 exhibits the following relative responsiveness to CysLTs: LTD4>LTC4>LTE4[8][9]

Ligands[edit]

The major CysLTs viz., LTC4, LTD4, and LTE4, are metabolites arachidonic acid made by the 5-lipoxygenase enzyme, ALOX5, mainly by cells involved in regulating inflammation, allergy, and other immune responses such as neutrophils, eosinophils, basophils, monocytes, macrophages, mast cells, dendritic cells, and B-lymphocytes. ALOX5 metabolizes arachidonic acid to the 5,6-epoxide precursor, LTA4, which is then acted on by LTC4 synthase which attaches the γ-glutamyl-cysteinyl-glycine tripeptide (i.e. glutathione) to carbon 6 of the intermediate thereby forming LTC4 synthase. LTC4 then exits its cells of origin through the MRP1 transporter (ABCC1) and is rapidly converted to LTD4 and then to LTE4) by cell surface-attached gamma-glutamyltransferase and dipeptidase peptidase enzymes by the sequential removal of the γ-glutamyl and then glycine residues.[10][11][5]

Clinical significance[edit]

In spite of the other receptors sited as being responsive to CysLTs, CysLTR1 appears to be critical in mediating many of the pathological responses to CysLTs in humans. Montelukast, Zafirlukast, and Pranlukast are selective receptor antagonists for the CysLT1. These drugs are in use and/or shown to be effective as prophalaxis and chronic treatments for allergic and non-allergic diseases such as: allergen-induced asthma and rhinitis; nonsteroidal anti-inflammatory drug-induced asthma and rhinitis (see Aspirin-induced asthma); exercise- and cold-air induced asthma (see Exercise-induced bronchoconstriction; and acquired childhood sleep apnea due to adenotonsillar hypertrophy (see Acquired non-inflammatory myopathy#Diet and Trauma Induced Myopathy.[10][11][12][13]

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b 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. 
  4. ^ a b c d e f 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. 
  5. ^ a b c Liu M, Yokomizo T (January 2015). "The role of leukotrienes in allergic diseases". Allergology International. 64 (1): 17–26. doi:10.1016/j.alit.2014.09.001. PMID 25572555. 
  6. ^ 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. PMID 27185938. 
  7. ^ 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 3630866free to read. PMID 23504326. 
  8. ^ Ciana P, Fumagalli M, Trincavelli ML, Verderio C, Rosa P, Lecca D, Ferrario S, Parravicini C, Capra V, Gelosa P, Guerrini U, Belcredito S, Cimino M, Sironi L, Tremoli E, Rovati GE, Martini C, Abbracchio MP (October 2006). "The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor". The EMBO Journal. 25 (19): 4615–27. doi:10.1038/sj.emboj.7601341. PMC 1589991free to read. PMID 16990797. 
  9. ^ Zhang LH, Zho JB, Wang YF (May 2008). "[Research advance in cysteinyl leukotriene receptors with brain injury]". Zhejiang Da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences (in Chinese). 37 (3): 315–20. PMID 18546539. 
  10. ^ a b 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. 
  11. ^ a b 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. PMID 24313690. 
  12. ^ 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. doi:10.1007/s00405-016-3983-8. PMID 26980339. 
  13. ^ 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. 

Further reading[edit]

  • Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN (January 2001). "Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses". The American Journal of Pathology. 158 (1): 3–9. doi:10.1016/S0002-9440(10)63937-5. PMC 1850279free to read. PMID 11141472. 
  • Sjöström M, Jakobsson PJ, Heimburger M, Palmblad J, Haeggström JZ (May 2001). "Human umbilical vein endothelial cells generate leukotriene C4 via microsomal glutathione S-transferase type 2 and express the CysLT(1) receptor". European Journal of Biochemistry / FEBS. 268 (9): 2578–86. doi:10.1046/j.1432-1327.2001.02142.x. PMID 11322876. 
  • Mellor EA, Maekawa A, Austen KF, Boyce JA (July 2001). "Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells". Proceedings of the National Academy of Sciences of the United States of America. 98 (14): 7964–9. doi:10.1073/pnas.141221498. PMC 35451free to read. PMID 11438743. 
  • Mita H, Hasegawa M, Saito H, Akiyama K (November 2001). "Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils". Clinical and Experimental Allergy. 31 (11): 1714–23. doi:10.1046/j.1365-2222.2001.01184.x. PMID 11696047. 
  • Shirasaki H, Kanaizumi E, Watanabe K, Matsui T, Sato J, Narita S, Rautiainen M, Himi T (July 2002). "Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa". Clinical and Experimental Allergy. 32 (7): 1007–12. doi:10.1046/j.1365-2222.2002.01425.x. PMID 12100046. 
  • Ohshima N, Nagase H, Koshino T, Miyamasu M, Yamaguchi M, Hirai K, Yamamoto K, Fujisawa T, Nakagawa N, Kishikawa K, Morita Y (September 2002). "A functional study on CysLT(1) receptors in human eosinophils". International Archives of Allergy and Immunology. 129 (1): 67–75. doi:10.1159/000065175. PMID 12373000. 
  • Ohd JF, Nielsen CK, Campbell J, Landberg G, Löfberg H, Sjölander A (January 2003). "Expression of the leukotriene D4 receptor CysLT1, COX-2, and other cell survival factors in colorectal adenocarcinomas". Gastroenterology. 124 (1): 57–70. doi:10.1053/gast.2003.50011. PMID 12512030. 
  • Chibana K, Ishii Y, Asakura T, Fukuda T (April 2003). "Up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin". Journal of Immunology. 170 (8): 4290–5. doi:10.4049/jimmunol.170.8.4290. PMID 12682264. 
  • Espinosa K, Bossé Y, Stankova J, Rola-Pleszczynski M (May 2003). "CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4". The Journal of Allergy and Clinical Immunology. 111 (5): 1032–40. doi:10.1067/mai.2003.1451. PMID 12743568. 
  • Walch L, Norel X, Gascard JP, Brink C (2003). "Arachidonic acid inhibits cysteinyl-leukotriene receptor activation in human pulmonary vessels". Advances in Experimental Medicine and Biology. 525: 75–9. doi:10.1007/978-1-4419-9194-2_15. PMID 12751740. 
  • Nielsen CK, Ohd JF, Wikström K, Massoumi R, Paruchuri S, Juhas M, Sjölander A (2003). "The leukotriene receptor CysLT1 and 5-lipoxygenase are upregulated in colon cancer". Advances in Experimental Medicine and Biology. 525: 201–4. doi:10.1007/978-1-4419-9194-2_43. PMID 12751768. 
  • Mechiche H, Naline E, Candenas L, Pinto FM, Birembault P, Advenier C, Devillier P (July 2003). "Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites". Clinical and Experimental Allergy. 33 (7): 887–94. doi:10.1046/j.1365-2222.2003.01696.x. PMID 12859443. 
  • Yang G, Haczku A, Chen H, Martin V, Galczenski H, Tomer Y, Van Besien CR, Evans JF, Panettieri RA, Funk CD, Van Beisen CR (May 2004). "Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4". American Journal of Physiology. Lung Cellular and Molecular Physiology. 286 (5): L992–1001. doi:10.1152/ajplung.00367.2003. PMID 15064240. 
  • Naik S, Billington CK, Pascual RM, Deshpande DA, Stefano FP, Kohout TA, Eckman DM, Benovic JL, Penn RB (March 2005). "Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling". The Journal of Biological Chemistry. 280 (10): 8722–32. doi:10.1074/jbc.M413014200. PMID 15590629. 
  • Corrigan C, Mallett K, Ying S, Roberts D, Parikh A, Scadding G, Lee T (February 2005). "Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis". The Journal of Allergy and Clinical Immunology. 115 (2): 316–22. doi:10.1016/j.jaci.2004.10.051. PMID 15696087. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.