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.

Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7

“…Using a loss‐of‐function murine model (CysLT 2 R‐LacZ), CysLT 2 receptor expression has been identified in neurons of the myenteric and submucosal plexus in the small intestine, colonic myenteric plexus, dorsal root ganglia and inferior ganglion of the vagal nerve (Barajas‐Espinosa et al ., ). In this model, LTC 4 /D 4 stimulation of colonic submucosal venules elicited a reduced permeability response in CysLT 2 receptor knockout (CysLT 2 −/− ) mice compared with WT mice, while basal neuronal activity of colonic‐projecting nociceptive neurons from dorsal root ganglia showed significantly higher excitability.…”

The cysteinyl leukotriene 2 receptor mediates retinal edema and pathological neovascularization in a murine model of oxygen‐induced retinopathy

“…Previous work by our laboratory demonstrated that activation of vascular CysLT 2 R in cremaster muscle venules leads to an exudation of fluorescein isothiocyanate (FITC)‐labeled albumin via a transcellular vesicle transport mechanism (8). As well, we have recently found that CysLT 2 R activation partially mediates vascular permeability following exogenous addition of cysLTs or inflammation in the colon that expresses CysLT 2 R in nonvascular niches (9). In this study, we identify the retinal vasculature as an expression site of CysLT 2 R and elucidate its involvement in retinal pathophysiology.…”

A Selective Cysteinyl Leukotriene Receptor 2 Antagonist Blocks Myocardial Ischemia/Reperfusion Injury and Vascular Permeability in Mice

“…CysLT 2 R has not received as much attention as CysLT 1 R, although there has been a wave of interest concerning this receptor in cardiovascular disease (Funk, 2005). CysLT 2 R is expressed in multiple organs in the mouse, including the heart (Jiang et al, 2008), brain, cremaster muscle vasculature , and myenteric neurons (Barajas-Espinosa et al, 2011). In humans, it is found in umbilical cord endothelial cells (Lötzer et al, 2003;Uzonyi et al, 2006), myocardium, and coronary vessels (Kamohara et al, 2001).…”