title: Inflammation-induced abnormalities in the subcellular localization and trafficking of the neurokinin 1 receptor in the enteric nervous system.
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 β-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 β-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 β-arrestin2 and downregulation of ECE-1. Internalized NK1R may generate sustained proinflammatory signals that disrupt normal neuronal functions.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Victoria, Australia; Daniel.Poole@monash.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Poole
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
authors.forename: TinaMarie
authors.initials: T
authors.lastname: Lieu
authors.affiliation: Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Pelayo
authors.affiliation: Population Health & Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; and Department of Laboratory Medicine, The University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Emily M
authors.initials: EM
authors.lastname: Eriksson
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Victoria, Australia; Department of Genetics, The University of Melbourne, Parkville, Victoria, Australia;
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Veldhuis
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; ARC Center of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Victoria, Australia; Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia; Department of Anaesthesia and Peri-operative Medicine, Monash University, Victoria, Australia.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D017615:Enteric Nervous System / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D018040:Receptors, Neurokinin-1; D000071557:beta-Arrestins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes
keywords: G protein-coupled receptor; inflammatory bowel disease; tachykinin