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NE reduces the expression of tight junctions (TJs) and aggravates intestinal mucosal damage, but the regulatory mechanism is still unclear. The present study aimed to investigate the molecular mechanisms underlying the regulation of stress-associated duodenal hyperpermeability by NE. Fluorescein isothiocyanate-dextran permeability, transepithelial resistance, immunofluorescence, Western blot, and high-performance liquid chromatography analysis were used in water-immersion restraint stress (WIRS) rats in this study. The results indicate that the duodenal permeability, degradation of TJs, mucosal NE, and \u03b2<jats:sub>2<\/jats:sub>-adrenergic receptor (\u03b2<jats:sub>2<\/jats:sub>-AR) increased in WIRS rats. The duodenal intracellular cyclic adenosine monophosphate levels were decreased, whereas the expression of \u03b2-arrestin 2 negatively regulates G protein-coupled receptors signaling, was significantly increased. Src recruitment was mediated by \u03b2-arrestin; thus, the levels of Src kinase activation were enhanced in WIRS rats. NE depletion, \u03b2<jats:sub>2<\/jats:sub>-AR, or \u03b2-arrestin 2 blockade significantly decreased mucosal permeability and increased TJs expression, suggesting improved mucosal barrier function. Moreover, NE induced an increased duodenal permeability of normal rats with activated \u03b2-arrestin 2\/Src signaling, which was significantly inhibited by \u03b2<jats:sub>2<\/jats:sub>-AR blockade. The present findings demonstrate that the enhanced NE induced an increased duodenal permeability in WIRS rats through the activated \u03b2<jats:sub>2<\/jats:sub>-AR\/\u03b2-arrestin 2\/Src pathway. This study provides novel insight into the molecular mechanism underlying the regulation of NE on the duodenal mucosal barrier and a new target for treating duodenal ulcers induced by stress. <\/jats:p>","DOI":"10.1152\/ajpcell.00412.2022","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T13:20:44Z","timestamp":1669641644000},"page":"C133-C141","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["NE-activated \u03b2<sub>2<\/sub>-AR\/\u03b2-arrestin 2\/Src pathway mediates duodenal hyperpermeability induced by water-immersion restraint stress"],"prefix":"10.1152","volume":"324","author":[{"given":"Jing-Ting","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China"},{"name":"Department of Anesthesiology, The First Affiliated Hospital of Shandong First 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