fbpx
Wikipedia

Cysteinyl leukotriene receptor 1

May 08, 2024

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see cysteinyl leukotrienes). CYSLTR1, 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 as well as models of the reactions in other animals.

CYSLTR1
Identifiers
AliasesCYSLTR1, CYSLT1, CYSLT1R, CYSLTR, HMTMF81, cysteinyl leukotriene receptor 1
External IDsOMIM: 300201 MGI: 1926218 HomoloGene: 4837 GeneCards: CYSLTR1
Orthologs
SpeciesHumanMouse
Entrez

10800

58861

Ensembl

ENSG00000173198

ENSMUSG00000052821

UniProt

Q9Y271

Q99JA4

RefSeq (mRNA)

NM_006639
NM_001282186
NM_001282187
NM_001282188

NM_001281859
NM_001281862
NM_021476

RefSeq (protein)

NP_001269115
NP_001269116
NP_001269117
NP_006630

NP_001268788
NP_001268791
NP_067451

Location (UCSC)Chr X: 78.27 – 78.33 MbChr X: 105.62 – 105.65 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene edit

The human CysLTR1 gene maps to the X chromosome at position Xq13-Xq21, 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.[5][6][7]

Expression edit

CYSLTR1 mRNA is expressed in lung smooth muscle, lung macrophages, monocytes, eosinophils, basophils, neutrophils, platelets, 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.[5][6][8]

Function edit

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 on the cell type. Acting through these G proteins and their subunits, ligand-bound CysLTR1 activates a series of pathways that lead to cell function; the order of potency of the cysLTs in stimulating CysLTR1 is LTD4>LTC4>LTE4[7] with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo.[6]

CysLTR1 activation by LTC4 and/or LTD4 in animal models and humans causes: airway bronchoconstriction and hyper-responsiveness to bronchoconstriction agents such as histamine; increased vascular permeability, edema, influx of eosinophils and neutrophils, smooth muscle proliferation, collagen deposition, and fibrosis in various tissue sites; and mucin secretion by goblet cells, goblet cell metaplasia, and epithelial cell hypertrophy in the membranes of the respiratory system.[7] Animal model and human tissue (preclinical studies) implicate CysLTR1 antagonists as having protective/reparative effects in models of brain injury (trauma-, ischemia-, and cold-induced), multiple sclerosis, auto-immune encephalomyelitis, Alzheimer's disease, and Parkinson's disease.[9] CysLTR1 activation is also associated in animal models with decreasing the blood–brain barrier (i.e. increasing the permeability of brain capillaries to elements of the blood's soluble elements) as well as promoting the movement of leukocytes for the blood to brain tissues; these effects may increase the development and frequency of epileptic seizure as well as the entry of leucocyte-borne viruses such as HIV-1 into brain tissue.[9]

Increased expression of CysLTR1 has been observed in transitional cell carcinoma of the urinary bladder, neuroblastoma and other brain cancers, prostate cancer, breast cancer, and colorectal cancer (CRC); indeed, CysLTR1 tumor expression is associated with poor survival prognoses in breast cancer and CRC patients, and drug inhibitors of CysLTR1 block the in vivo and in vivo (animal model) growth of CRC cells and tumors, respectively. The pro-cancer effects of CysLTR1 in CRC appear due to its ability to up-regulate pathways that increase in CRC cell proliferation and survival.[10][11]

Other cysLT receptors include cysteinyl leukotriene receptor 2 (i.e. CysLTR2) and GPR99 (also termed the oxoglutarate receptor and, sometimes, CysLTR3).[6] The order of potency of the cysLTs in stimulating CysLTR2 is LTD4=LTC4>LTE4[7] with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR2 in vivo.[6] GPR99 appears to be an important receptor for CysLTs, particularly for LTE4. The CysLTs show relative potencies of LTE4>LTC4>LTD4 in stimulating GPR99-bearing cells with GPR99-deficient mice exhibiting a dose-dependent loss of vascular permeability responses in skin to LTE4 but not to LTC4 or LTD4. This and other data suggest that GPR99 is an important receptor for the in vivo actions of LTE4 but not LTD4 or LTC4[6][12][13]

The GPR17 receptor, also termed the uracil nucleotide/cysteinyl leukotriene receptor, was initially defined as a receptor for LTC4, LTD4, and uracil nucleotides. However, more recent studies from different laboratories could not confirm these results; they found that GPR17-bearing cells did not respond to these CysLTs or nucleotides but did find that cells expressing both CysLTR1 and GPR17 receptors exhibited a marked reduction in binding LTC4 and that mice lacking GPR17 were hyper-responsive to igE-induced passive cutaneous anaphylaxis. GPR17 therefore appears to inhibit CysLTR1, at least in these model systems.[14] In striking contrast to these studies, studies concentration on neural tissues continue to find that Oligodendrocyte progenitor cells express GPR17 and respond through this receptor to LTC4, LTD4, and certain purines (see GPR17#Function).

The Purinergic receptor, P2Y12, while not directly binding or responding to CysLTs, appears to be activated as a consequence of activating CysLT1: blockage of P2Y12 activation either by receptor depletion or pharmacological methods inhibits many of the CysLTR1-dependent actions of CysLTs in various cell types in vitro as well as in an animal model of allergic disease.[8][15][16][9]

Ligands edit

The major CysLTs viz., LTC4, LTD4, and LTE4, are metabolites of 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.[7][17][18]

Gene polymorphism edit

927T/C (nucleotide thymine replaces cytosine at position 97 of the CysLTR1 gene) gene polymorphism in the coding region of CysLTR1 has been shown to be predictive of the severity of atopy (i.e. a predisposition toward developing certain allergic hypersensitivity reactions), but not associated with asthma, in a population of 341 Caucasians in afflicted sib-pair families from the Southampton area in the United Kingdom. This atopy severity was most apparent in female siblings but the incidence of this polymorphism is extremely low and the functionality of the 927T/C gene and its product protein are as yet unknown.[19][20]

The population of the small remote far South Atlantic Ocean island of Tristan da Cunha (266 permanent, genetically isolated residents) suffers a high prevalence of atopy and asthma. The CysLTR1 gene product variant, 300G/S (i.e. amino acid glycine replaces serine at the 300 position of the CysLTR1 protein), has been shown to be significantly associated with atopy in this population. The CysLTR1 300S variant exhibited significant increased sensitivity to LTD4 and LTC4 suggesting that this hypersensitivity underlies its association with atopy.[21][22]

Clinical significance edit

In spite of the other receptors cited 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 CysLTR1 but not CysLTR2. These drugs are in use and/or shown to be effective as prophylaxis and chronic treatments for allergic and non-allergic diseases such as: allergen-induced asthma and rhinitis; aspirin-exacerbated respiratory disease; exercise- and cold-air induced asthma (see Exercise-induced bronchoconstriction); and childhood sleep apnea due to adenotonsillar hypertrophy (see Acquired non-inflammatory myopathy#Diet and Trauma Induced Myopathy).[17][18][23][24] However, responses to these lukast drugs vary greatly with the drugs showing fairly high rates of poor responses and ~20% of patients reporting no change in symptoms after treatment with these agents.[13][25][26] It seems possible that the responses of CysLTR2, GPR99, or other receptors to CysLT's may be contributing to these diseases.[8][15]

See also edit

References edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000173198 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000052821 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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. S2CID 23133928.
  6. ^ 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. S2CID 11433313.
  7. ^ a b c d e 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.
  8. ^ a b c 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. S2CID 206159450.
  9. ^ a b c Ghosh A, Chen F, Thakur A, Hong H (2016). "Cysteinyl Leukotrienes and Their Receptors: Emerging Therapeutic Targets in Central Nervous System Disorders". CNS Neuroscience & Therapeutics. 22 (12): 943–951. doi:10.1111/cns.12596. PMC 6492851. PMID 27542570.
  10. ^ Singh RK, Gupta S, Dastidar S, Ray A (2010). "Cysteinyl leukotrienes and their receptors: molecular and functional characteristics". Pharmacology. 85 (6): 336–49. doi:10.1159/000312669. PMID 20516735.
  11. ^ Savari S, Vinnakota K, Zhang Y, Sjölander A (2014). "Cysteinyl leukotrienes and their receptors: bridging inflammation and colorectal cancer". World Journal of Gastroenterology. 20 (4): 968–77. doi:10.3748/wjg.v20.i4.968. PMC 3921548. PMID 24574769.
  12. ^ 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. Bibcode:2016PNAS..113.6242B. doi:10.1073/pnas.1605957113. PMC 4896673. PMID 27185938.
  13. ^ a b 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.
  14. ^ 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.
  15. ^ a b 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.
  16. ^ Baptista-dos-Reis R, Muniz VS, Neves JS (2015). "Multifaceted roles of cysteinyl leukotrienes in eliciting eosinophil granule protein secretion". BioMed Research International. 2015: 1–7. doi:10.1155/2015/848762. PMC 4383494. PMID 25866815.
  17. ^ 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.
  18. ^ 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. doi:10.2174/1389450114666131209110745. PMID 24313690.
  19. ^ Allen BW (1980). "Inhibitory effect of rubber on the growth of M. tuberculosis". Tubercle. 61 (2): 91–5. doi:10.1016/0041-3879(80)90016-1. PMID 6776674.
  20. ^ "WikiGenes - Collaborative Publishing". WikiGenes - Collaborative Publishing.
  21. ^ Thompson MD, Capra V, Takasaki J, Maresca G, Rovati GE, Slutsky AS, Lilly C, Zamel N, McIntyre Burnham W, Cole DE, Siminovitch KA (2007). "A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate". Pharmacogenetics and Genomics. 17 (7): 539–49. doi:10.1097/FPC.0b013e328012d0bf. PMID 17558309. S2CID 43781411.
  22. ^ Yaddaden L, Véronneau S, Thompson MD, Rola-Pleszczynski M, Stankova J (2016). "Cellular signalling of cysteinyl leukotriene type 1 receptor variants CysLT₁-G300S and CysLT₁-I206S". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 105: 1–8. doi:10.1016/j.plefa.2015.12.004. PMID 26869085.
  23. ^ 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 (12): 4111–4117. doi:10.1007/s00405-016-3983-8. PMID 26980339. S2CID 31311115.
  24. ^ 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.
  25. ^ 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. S2CID 27541608.
  26. ^ Szefler SJ, Phillips BR, Martinez FD, Chinchilli VM, Lemanske RF, Strunk RC, Zeiger RS, Larsen G, Spahn JD, Bacharier LB, Bloomberg GR, Guilbert TW, Heldt G, Morgan WJ, Moss MH, Sorkness CA, Taussig LM (2005). "Characterization of within-subject responses to fluticasone and montelukast in childhood asthma". The Journal of Allergy and Clinical Immunology. 115 (2): 233–42. doi:10.1016/j.jaci.2004.11.014. PMID 15696076.

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 1850279. 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. 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. Bibcode:2001PNAS...98.7964M. doi:10.1073/pnas.141221498. PMC 35451. 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. S2CID 43278015.
  • 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. S2CID 25871662.
  • 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. S2CID 11948102.
  • 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 Prostaglandin, Leukotriene, and other Bioactive Lipid Research. Advances in Experimental Medicine and Biology. Vol. 525. pp. 75–9. doi:10.1007/978-1-4419-9194-2_15. ISBN 978-1-4613-4831-3. 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 Prostaglandin, Leukotriene, and other Bioactive Lipid Research. Advances in Experimental Medicine and Biology. Vol. 525. pp. 201–4. doi:10.1007/978-1-4419-9194-2_43. ISBN 978-1-4613-4831-3. 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. S2CID 37457415.
  • 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

  • . IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-05.
  • Overview of all the structural information available in the PDB for UniProt: Q9Y271 (Cysteinyl leukotriene receptor 1) at the PDBe-KB.

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

May 08, 2024
cysteinyl, leukotriene, receptor, also, termed, cysltr1, receptor, cysteinyl, leukotrienes, cysteinyl, leukotrienes, cysltr1, binding, these, cysteinyl, cyslts, ltc4, ltd4, much, lesser, extent, lte4, contributes, mediating, various, allergic, hypersensitivity. Cysteinyl leukotriene receptor 1 also termed CYSLTR1 is a receptor for cysteinyl leukotrienes LT see cysteinyl leukotrienes CYSLTR1 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 as well as models of the reactions in other animals CYSLTR1IdentifiersAliasesCYSLTR1 CYSLT1 CYSLT1R CYSLTR HMTMF81 cysteinyl leukotriene receptor 1External IDsOMIM 300201 MGI 1926218 HomoloGene 4837 GeneCards CYSLTR1Gene location Human Chr X chromosome human 1 BandXq21 1Start78 271 468 bp 1 End78 327 691 bp 1 Gene location Mouse Chr X chromosome mouse 2 BandX X DStart105 617 952 bp 2 End105 647 285 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inmonocytesuperficial temporal arterybone marrowlymph nodebloodpalpebral conjunctivaAchilles tendongallbladderrectumspleenTop expressed insciatic nervecarotid bodymucosa of small intestineanklewhite adipose tissueyolk sacileumabdominal wallesophaguslipMore reference expression dataBioGPSn aGene ontologyMolecular functionG protein coupled peptide receptor activity G protein coupled receptor activity leukotriene receptor activity signal transducer activity protein binding galanin receptor activityCellular componentintegral component of membrane membrane plasma membrane integral component of plasma membraneBiological processdefense response positive regulation of cytosolic calcium ion concentration respiratory gaseous exchange by respiratory system chemotaxis phospholipase C activating G protein coupled receptor signaling pathway cell surface receptor signaling pathway leukotriene signaling pathway circulatory system process neuropeptide signaling pathway calcium ion transport signal transduction inflammatory response to antigenic stimulus G protein coupled receptor signaling pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez1080058861EnsemblENSG00000173198ENSMUSG00000052821UniProtQ9Y271Q99JA4RefSeq mRNA NM 006639NM 001282186NM 001282187NM 001282188NM 001281859NM 001281862NM 021476RefSeq protein NP 001269115NP 001269116NP 001269117NP 006630NP 001268788NP 001268791NP 067451Location UCSC Chr X 78 27 78 33 MbChr X 105 62 105 65 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Gene 2 Expression 3 Function 4 Ligands 5 Gene polymorphism 6 Clinical significance 7 See also 8 References 9 Further reading 10 External linksGene editThe human CysLTR1 gene maps to the X chromosome at position Xq13 Xq21 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 5 6 7 Expression editCYSLTR1 mRNA is expressed in lung smooth muscle lung macrophages monocytes eosinophils basophils neutrophils platelets 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 5 6 8 Function editCysLTR1 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 on the cell type Acting through these G proteins and their subunits ligand bound CysLTR1 activates a series of pathways that lead to cell function the order of potency of the cysLTs in stimulating CysLTR1 is LTD4 gt LTC4 gt LTE4 7 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo 6 CysLTR1 activation by LTC4 and or LTD4 in animal models and humans causes airway bronchoconstriction and hyper responsiveness to bronchoconstriction agents such as histamine increased vascular permeability edema influx of eosinophils and neutrophils smooth muscle proliferation collagen deposition and fibrosis in various tissue sites and mucin secretion by goblet cells goblet cell metaplasia and epithelial cell hypertrophy in the membranes of the respiratory system 7 Animal model and human tissue preclinical studies implicate CysLTR1 antagonists as having protective reparative effects in models of brain injury trauma ischemia and cold induced multiple sclerosis auto immune encephalomyelitis Alzheimer s disease and Parkinson s disease 9 CysLTR1 activation is also associated in animal models with decreasing the blood brain barrier i e increasing the permeability of brain capillaries to elements of the blood s soluble elements as well as promoting the movement of leukocytes for the blood to brain tissues these effects may increase the development and frequency of epileptic seizure as well as the entry of leucocyte borne viruses such as HIV 1 into brain tissue 9 Increased expression of CysLTR1 has been observed in transitional cell carcinoma of the urinary bladder neuroblastoma and other brain cancers prostate cancer breast cancer and colorectal cancer CRC indeed CysLTR1 tumor expression is associated with poor survival prognoses in breast cancer and CRC patients and drug inhibitors of CysLTR1 block the in vivo and in vivo animal model growth of CRC cells and tumors respectively The pro cancer effects of CysLTR1 in CRC appear due to its ability to up regulate pathways that increase in CRC cell proliferation and survival 10 11 Other cysLT receptors include cysteinyl leukotriene receptor 2 i e CysLTR2 and GPR99 also termed the oxoglutarate receptor and sometimes CysLTR3 6 The order of potency of the cysLTs in stimulating CysLTR2 is LTD4 LTC4 gt LTE4 7 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR2 in vivo 6 GPR99 appears to be an important receptor for CysLTs particularly for LTE4 The CysLTs show relative potencies of LTE4 gt LTC4 gt LTD4 in stimulating GPR99 bearing cells with GPR99 deficient mice exhibiting a dose dependent loss of vascular permeability responses in skin to LTE4 but not to LTC4 or LTD4 This and other data suggest that GPR99 is an important receptor for the in vivo actions of LTE4 but not LTD4 or LTC4 6 12 13 The GPR17 receptor also termed the uracil nucleotide cysteinyl leukotriene receptor was initially defined as a receptor for LTC4 LTD4 and uracil nucleotides However more recent studies from different laboratories could not confirm these results they found that GPR17 bearing cells did not respond to these CysLTs or nucleotides but did find that cells expressing both CysLTR1 and GPR17 receptors exhibited a marked reduction in binding LTC4 and that mice lacking GPR17 were hyper responsive to igE induced passive cutaneous anaphylaxis GPR17 therefore appears to inhibit CysLTR1 at least in these model systems 14 In striking contrast to these studies studies concentration on neural tissues continue to find that Oligodendrocyte progenitor cells express GPR17 and respond through this receptor to LTC4 LTD4 and certain purines see GPR17 Function The Purinergic receptor P2Y12 while not directly binding or responding to CysLTs appears to be activated as a consequence of activating CysLT1 blockage of P2Y12 activation either by receptor depletion or pharmacological methods inhibits many of the CysLTR1 dependent actions of CysLTs in various cell types in vitro as well as in an animal model of allergic disease 8 15 16 9 Ligands editThe major CysLTs viz LTC4 LTD4 and LTE4 are metabolites of 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 g 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 g glutamyl and then glycine residues 7 17 18 Gene polymorphism edit927T C nucleotide thymine replaces cytosine at position 97 of the CysLTR1 gene gene polymorphism in the coding region of CysLTR1 has been shown to be predictive of the severity of atopy i e a predisposition toward developing certain allergic hypersensitivity reactions but not associated with asthma in a population of 341 Caucasians in afflicted sib pair families from the Southampton area in the United Kingdom This atopy severity was most apparent in female siblings but the incidence of this polymorphism is extremely low and the functionality of the 927T C gene and its product protein are as yet unknown 19 20 The population of the small remote far South Atlantic Ocean island of Tristan da Cunha 266 permanent genetically isolated residents suffers a high prevalence of atopy and asthma The CysLTR1 gene product variant 300G S i e amino acid glycine replaces serine at the 300 position of the CysLTR1 protein has been shown to be significantly associated with atopy in this population The CysLTR1 300S variant exhibited significant increased sensitivity to LTD4 and LTC4 suggesting that this hypersensitivity underlies its association with atopy 21 22 Clinical significance editIn spite of the other receptors cited 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 CysLTR1 but not CysLTR2 These drugs are in use and or shown to be effective as prophylaxis and chronic treatments for allergic and non allergic diseases such as allergen induced asthma and rhinitis aspirin exacerbated respiratory disease exercise and cold air induced asthma see Exercise induced bronchoconstriction and childhood sleep apnea due to adenotonsillar hypertrophy see Acquired non inflammatory myopathy Diet and Trauma Induced Myopathy 17 18 23 24 However responses to these lukast drugs vary greatly with the drugs showing fairly high rates of poor responses and 20 of patients reporting no change in symptoms after treatment with these agents 13 25 26 It seems possible that the responses of CysLTR2 GPR99 or other receptors to CysLT s may be contributing to these diseases 8 15 See also editEicosanoid receptor Cysteinyl leukotriene receptor 2 GPR99References edit a b c GRCh38 Ensembl release 89 ENSG00000173198 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000052821 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine 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 S2CID 23133928 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 S2CID 11433313 a b c d e 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 a b c 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 S2CID 206159450 a b c Ghosh A Chen F Thakur A Hong H 2016 Cysteinyl Leukotrienes and Their Receptors Emerging Therapeutic Targets in Central Nervous System Disorders CNS Neuroscience amp Therapeutics 22 12 943 951 doi 10 1111 cns 12596 PMC 6492851 PMID 27542570 Singh RK Gupta S Dastidar S Ray A 2010 Cysteinyl leukotrienes and their receptors molecular and functional characteristics Pharmacology 85 6 336 49 doi 10 1159 000312669 PMID 20516735 Savari S Vinnakota K Zhang Y Sjolander A 2014 Cysteinyl leukotrienes and their receptors bridging inflammation and colorectal cancer World Journal of Gastroenterology 20 4 968 77 doi 10 3748 wjg v20 i4 968 PMC 3921548 PMID 24574769 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 Bibcode 2016PNAS 113 6242B doi 10 1073 pnas 1605957113 PMC 4896673 PMID 27185938 a b 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 Kanaoka Y Boyce JA 2014 Cysteinyl leukotrienes and their receptors emerging concepts Allergy Asthma amp Immunology Research 6 4 288 95 doi 10 4168 aair 2014 6 4 288 PMC 4077954 PMID 24991451 a b 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 Baptista dos Reis R Muniz VS Neves JS 2015 Multifaceted roles of cysteinyl leukotrienes in eliciting eosinophil granule protein secretion BioMed Research International 2015 1 7 doi 10 1155 2015 848762 PMC 4383494 PMID 25866815 a b Haeggstrom 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 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 doi 10 2174 1389450114666131209110745 PMID 24313690 Allen BW 1980 Inhibitory effect of rubber on the growth of M tuberculosis Tubercle 61 2 91 5 doi 10 1016 0041 3879 80 90016 1 PMID 6776674 WikiGenes Collaborative Publishing WikiGenes Collaborative Publishing Thompson MD Capra V Takasaki J Maresca G Rovati GE Slutsky AS Lilly C Zamel N McIntyre Burnham W Cole DE Siminovitch KA 2007 A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate Pharmacogenetics and Genomics 17 7 539 49 doi 10 1097 FPC 0b013e328012d0bf PMID 17558309 S2CID 43781411 Yaddaden L Veronneau S Thompson MD Rola Pleszczynski M Stankova J 2016 Cellular signalling of cysteinyl leukotriene type 1 receptor variants CysLT G300S and CysLT I206S Prostaglandins Leukotrienes and Essential Fatty Acids 105 1 8 doi 10 1016 j plefa 2015 12 004 PMID 26869085 Kar M Altintoprak 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 12 4111 4117 doi 10 1007 s00405 016 3983 8 PMID 26980339 S2CID 31311115 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 Gueant 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 Thompson MD Takasaki J Capra V Rovati GE Siminovitch KA Burnham WM Hudson TJ Bosse Y Cole DE 2006 G protein coupled receptors and asthma endophenotypes the cysteinyl leukotriene system in perspective Molecular Diagnosis amp Therapy 10 6 353 66 doi 10 1007 bf03256212 PMID 17154652 S2CID 27541608 Szefler SJ Phillips BR Martinez FD Chinchilli VM Lemanske RF Strunk RC Zeiger RS Larsen G Spahn JD Bacharier LB Bloomberg GR Guilbert TW Heldt G Morgan WJ Moss MH Sorkness CA Taussig LM 2005 Characterization of within subject responses to fluticasone and montelukast in childhood asthma The Journal of Allergy and Clinical Immunology 115 2 233 42 doi 10 1016 j jaci 2004 11 014 PMID 15696076 Further reading editGronert 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 1850279 PMID 11141472 Sjostrom M Jakobsson PJ Heimburger M Palmblad J Haeggstrom 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 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 Bibcode 2001PNAS 98 7964M doi 10 1073 pnas 141221498 PMC 35451 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 S2CID 43278015 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 S2CID 25871662 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 S2CID 11948102 Ohd JF Nielsen CK Campbell J Landberg G Lofberg H Sjolander 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 Bosse 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 Prostaglandin Leukotriene and other Bioactive Lipid Research Advances in Experimental Medicine and Biology Vol 525 pp 75 9 doi 10 1007 978 1 4419 9194 2 15 ISBN 978 1 4613 4831 3 PMID 12751740 Nielsen CK Ohd JF Wikstrom K Massoumi R Paruchuri S Juhas M Sjolander A 2003 The Leukotriene Receptor CYSLT1 and 5 Lipoxygenase Are Upregulated in Colon Cancer Advances in Prostaglandin Leukotriene and other Bioactive Lipid Research Advances in Experimental Medicine and Biology Vol 525 pp 201 4 doi 10 1007 978 1 4419 9194 2 43 ISBN 978 1 4613 4831 3 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 S2CID 37457415 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 Leukotriene Receptors CysLT1 IUPHAR Database of Receptors and Ion Channels International Union of Basic and Clinical Pharmacology Archived from the original on 2016 03 03 Retrieved 2008 12 05 Overview of all the structural information available in the PDB for UniProt Q9Y271 Cysteinyl leukotriene receptor 1 at the PDBe KB This article incorporates text from the United States National Library of Medicine which is in the public domain Retrieved from https en wikipedia org w index php title Cysteinyl leukotriene receptor 1 amp oldid 1193259832, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.