Cysteinyl leukotriene receptor 1
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; 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. Gene The human 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. Expression 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. Function 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 (see Gq alpha subunit#function and Ga subunit#function for details); the order of potency of the in stimulating CysLTR1 is LTD4>LTC4>LTE4 with LTE4 probably lacking sufficient potency to have much activity that operates through CysLTR1 in vivo. 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. 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. 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. 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. Other cysLT receptors include cysteinyl leukotriene receptor