ArticleProceedings of the National Academy of Sciences of the United States of America2007
Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 82 citations in OpenAlex.
- Endothelin-converting enzyme 2 regulates κ opioid receptor trafficking and function.The Journal of pharmacology and experimental therapeutics · 2025Article
- Clearing Amyloid-Beta by Astrocytes: The Role of Rho GTPases Signaling Pathways as Potential Therapeutic Targets.Brain sciences · 2024Review
- Functional consequences of spatial, temporal and ligand bias of G protein-coupled receptors.Nature reviews. Nephrology · 2024Review
- Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Modulating the tachykinin: Role of substance P and neurokinin receptor expression in ocular surface disorders.The ocular surface · 2022Review
- Article
- A Novel Mechanism of Endoplasmic Reticulum Stress- and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Article
- Compartment-specific opioid receptor signaling is selectively modulated by different dynorphin peptides.eLife · 2021Article
- Comparative Cell Surface Proteomic Analysis of the Primary Human T Cell and Monocyte Responses to Type I Interferon.Frontiers in immunology · 2021Article
- G-Protein-Coupled Receptors Are Dynamic Regulators of Digestion and Targets for Digestive Diseases.Gastroenterology · 2019Review
- International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.Pharmacological reviews · 2018Review
- Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors.Trends in pharmacological sciences · 2018Review
- Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief.Science translational medicine · 2017Article
- Neurokinin-1 receptor is a novel positive regulator of Wnt/ β-catenin signaling in melanogenesis.Oncotarget · 2016Article
- Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis.Experimental and molecular pathology · 2016Article
- Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane.The Journal of biological chemistry · 2016Article
- Inflammation-induced abnormalities in the subcellular localization and trafficking of the neurokinin 1 receptor in the enteric nervous system.American journal of physiology. Gastrointestinal and liver physiology · 2015Article
- Substance P stimulates endothelin 1 secretion via endothelin-converting enzyme 1 and promotes melanogenesis in human melanocytes.The Journal of investigative dermatology · 2015Article
- Endothelin-converting enzyme 2 differentially regulates opioid receptor activity.British journal of pharmacology · 2015Article
- Endothelin-converting enzyme 1 and β-arrestins exert spatiotemporal control of substance P-induced inflammatory signals.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.