title: Characterization of the cysteinyl leukotriene 2 receptor in novel expression sites of the gastrointestinal tract.
abstract: Cysteinyl leukotrienes (cysLTs: LTC₄, LTD₄, and LTE₄) are pro-inflammatory lipid molecules synthesized from arachidonic acid. They exert their actions on at least two cysLT receptors (CysLT₁R and CysLT₂R). Endothelial expression and activation of these receptors is linked to vasoactive responses and to the promotion of vascular permeability. Here we track the expression pattern of CysLT₂R in a loss-of-function murine model (CysLT₂R-LacZ) to neurons of the myenteric and submucosal plexus in the small intestine, colonic myenteric plexus, dorsal root ganglia, and nodose ganglion. Cysteinyl leukotriene (LTC₄/D₄) stimulation of colonic submucosal venules elicited a greater permeability response in wild-type mice. In a dextran sulfate sodium-induced colon inflammation model, the disease activity index and colonic edema (measured by wet:dry weights and submucosal thickness) were significantly reduced in knockout (KO) mice compared to controls. Tumor necrosis factor-α levels in colon tissue were significantly lower in KO mice; however, myeloperoxidase activity was similar in both the KO and wild-type groups. Finally, patch-clamp recordings of basal neuronal activity of colonic-projecting nociceptive neurons from dorsal root ganglia (T9-13) revealed significantly higher excitability in KO neurons compared to wild type. These results suggest that a lack of neuronal expression of CysLT₂R in the murine colonic myenteric plexus attenuates colitis disease progression via a reduction in inflammation-associated tissue edema and increases neuronal sensitivity to nociceptive stimuli.
authors.affiliation: Department of Physiology and Biochemistry, Queen's University, Kingston, Ontario, Canada.
authors.forename: Alma
authors.initials: A
authors.lastname: Barajas-Espinosa
authors.forename: Fernando
authors.initials: F
authors.lastname: Ochoa-Cortes
authors.forename: Michael P
authors.initials: MP
authors.lastname: Moos
authors.forename: F Daniel
authors.initials: FD
authors.lastname: Ramirez
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Vanner
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003092:Colitis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D003545:Cysteine / Q000494:pharmacology; D016264:Dextran Sulfate; D004487:Edema / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D005119:Extravasation of Diagnostic and Therapeutic Materials; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015289:Leukotrienes / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018077:Receptors, Leukotriene / Q000172:deficiency / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014699:Venules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: C518288:FITC-albumin; D015289:Leukotrienes; D018077:Receptors, Leukotriene; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; C112381:cysteinyl-leukotriene; D016264:Dextran Sulfate; C412375:cysteinyl leukotriene receptor 2; D016650:Fluorescein-5-isothiocyanate; D003545:Cysteine