title: Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling.
abstract: Neuropeptide signaling requires the presence of G protein-coupled receptors (GPCRs) at the cell surface. Activated GPCRs interact with beta-arrestins, which mediate receptor desensitization, endocytosis, and mitogenic signaling, and the peptide-receptor-arrestin complex is sequestered into endosomes. Although dissociation of beta-arrestins is required for receptor recycling and resensitization, the critical event that initiates this process is unknown. Here we report that the agonist availability in the endosomes, controlled by the membrane metalloendopeptidase endothelin-converting enzyme 1 (ECE-1), determines stability of the peptide-receptor-arrestin complex and regulates receptor recycling and resensitization. Substance P (SP) binding to the tachykinin neurokinin 1 receptor (NK1R) induced membrane translocation of beta-arrestins followed by trafficking of the SP-NK1R-beta-arrestin complex to early endosomes containing ECE-1a-d. ECE-1 degraded SP in acidified endosomes, disrupting the complex; beta-arrestins returned to the cytosol, and the NK1R, freed from beta-arrestins, recycled and resensitized. An ECE-1 inhibitor, by preventing NK1R recycling in endothelial cells, inhibited resensitization of SP-induced inflammation. This mechanism is a general one because ECE-1 similarly regulated NK3R resensitization. Thus, peptide availability in endosomes, here regulated by ECE-1, determines the stability of the peptide-receptor-arrestin complex. This mechanism regulates receptor recycling, which is necessary for sustained signaling, and it may also control beta-arrestin-dependent mitogenic signaling of endocytosed receptors. We propose that other endosomal enzymes and transporters may similarly control the availability of transmitters in endosomes to regulate trafficking and signaling of GPCRs. Antagonism of these endosomal processes represents a strategy for inhibiting sustained signaling of receptors, and defects may explain the tachyphylaxis of drugs that are receptor agonists.
authors.affiliation: Department of Dermatology, Interdisziplinäres Zentrum für Klinische Forschung Münster, and Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Von-Esmarch-Strasse 58, 48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Roosterman
authors.forename: Graeme S
authors.initials: GS
authors.lastname: Cottrell
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Padilla
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Eckman
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000502:physiology*; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D009479:Neuropeptides; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes