Cysteinyl leukotriene receptor 1
|, CYSLT1, CYSLT1R, CYSLTR, HMTMF81, cysteinyl leukotriene receptor 1|
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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.
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.
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.
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 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo.
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). 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 CysLTR2 in vivo. 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. GPR17 exhibits the following relative responsiveness to CysLTs: LTD4>LTC4>LTE4
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.
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.
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