Inflammation-induced abnormalities in the subcellular localization and trafficking of the neurokinin 1 receptor in the enteric nervous system

Poole, DP; Lieu, T; Pelayo, JC; Eriksson, EM; Veldhuis, NA; Bunnett, NW

Author(s): Poole, DP; Lieu, T; Pelayo, JC; Eriksson, EM; Veldhuis, NA; Bunnett, NW;
Details: Publication Year 2015-08-15,Volume 309,Issue #4,Page G248-59
Journal Title: Am J Physiol Gastrointest Liver Physiol
Publication Type: Journal Article
Abstract: Activated G protein-coupled receptors traffic to endosomes and are sorted to recycling or degradative pathways. Endosomes are also a site of receptor signaling of sustained and pathophysiologically important processes, including inflammation. However, the mechanisms of endosomal sorting of receptors and the impact of disease on trafficking have not been fully defined. We examined the effects of inflammation on the subcellular distribution and trafficking of the substance P (SP) neurokinin 1 receptor (NK1R) in enteric neurons. We studied NK1R trafficking in enteric neurons of the mouse colon using immunofluorescence and confocal microscopy. The impact of inflammation was studied in IL10(-/-)-piroxicam and trinitrobenzenesulfonic acid colitis models. NK1R was localized to the plasma membrane of myenteric and submucosal neurons of the uninflamed colon. SP evoked NK1R endocytosis and recycling. Deletion of beta-arrestin2, which associates with the activated NK1R, accelerated recycling. Inhibition of endothelin-converting enzyme-1 (ECE-1), which degrades endosomal SP, prevented recycling. Inflammation was associated with NK1R endocytosis in myenteric but not submucosal neurons. Whereas the NK1R in uninflamed neurons recycled within 60 min, NK1R recycling in inflamed neurons was delayed for >120 min, suggesting defective recycling machinery. Inflammation was associated with beta-arrestin2 upregulation and ECE-1 downregulation, which may contribute to the defective NK1R recycling. We conclude that inflammation evokes redistribution of NK1R from the plasma membrane to endosomes of myenteric neurons through enhanced SP release and defective NK1R recycling. Defective recycling may be secondary to upregulation of beta-arrestin2 and downregulation of ECE-1. Internalized NK1R may generate sustained proinflammatory signals that disrupt normal neuronal functions.
Publisher: American Physiological Society
Research Division(s): Population Health And Immunity
PubMed ID: 26138465
Publisher's Version: https://doi.org/10.1152/ajpgi.00118.2015
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2015-09-24 02:12:27

Last Modified: 2019-04-01 08:59:20