Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling

Roosterman, D., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, Padilla, B. E., Muller, L., Eckman, C. B., Bunnett, N. W. and Steinhoff, M. (2007) Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling. Proceedings of the National Academy of Sciences of the United States of America, 104 (28). pp. 11838-11843. ISSN 0027-8424 doi: 10.1073/pnas.0701910104

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/30264
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology No Reading authors. Back catalogue items
Uncontrolled Keywords	Animals, Arrestins/metabolism, Aspartic Acid Endopeptidases/*physiology, Cells, Cultured Endocytosis/physiology, Endosomes/*metabolism, Humans, Male, Metalloendopeptidases/*physiology, Mice, Mice, Inbred C57BL Neuropeptides/*metabolism/physiology, Protein Isoforms/metabolism, Protein Transport/physiology Receptors, G-Protein-Coupled/*metabolism, Signal Transduction/physiology
Publisher	National Academy of Sciences
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