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Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins

Padilla, B. E., Cottrell, G. S., Roosterman, D., Pikios, S., Muller, L., Steinhoff, M. and Bunnett, N. W. (2007) Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. Journal of Cell Biology, 179 (5). pp. 981-997. ISSN 0021-9525

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To link to this item DOI: 10.1083/jcb.200704053

Abstract/Summary

Although cell surface metalloendopeptidases degrade neuropeptides in the extracellular fluid to terminate signaling, the function of peptidases in endosomes is unclear. We report that isoforms of endothelin-converting enzyme-1 (ECE-1a-d) are present in early endosomes, where they degrade neuropeptides and regulate post-endocytic sorting of receptors. Calcitonin gene-related peptide (CGRP) co-internalizes with calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), beta-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP. CGRP degradation promotes CLR/RAMP1 recycling and beta-arrestin2 redistribution to the cytosol. ECE-1 inhibition or knockdown traps CLR/RAMP1 and beta-arrestin2 in endosomes and inhibits CLR/RAMP1 recycling and resensitization, whereas ECE-1 overexpression has the opposite effect. ECE-1 does not regulate either the resensitization of receptors for peptides that are not ECE-1 substrates (e.g., angiotensin II), or the recycling of the bradykinin B(2) receptor, which transiently interacts with beta-arrestins. We propose a mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/beta-arrestin complex, freeing internalized receptors from beta-arrestins and promoting recycling and resensitization.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30265
Uncontrolled Keywords:Angiotensin I/metabolism Angiotensin II/metabolism Animals Arrestins/*metabolism Aspartic Acid Endopeptidases/antagonists & inhibitors/*metabolism Bradykinin/metabolism Calcitonin Gene-Related Peptide/metabolism Calcitonin Receptor-Like Protein Cell Line, Tumor Cell Membrane/drug effects/metabolism Endocytosis/drug effects Endosomes/drug effects/*enzymology Enzyme Inhibitors/pharmacology Humans Hydrogen-Ion Concentration/drug effects Hydrolysis/drug effects Intracellular Signaling Peptides and Proteins/metabolism Isoenzymes/metabolism Membrane Proteins/metabolism Metalloendopeptidases/antagonists & inhibitors/*metabolism Protein Binding/drug effects Protein Transport/drug effects Rats Receptor Activity-Modifying Protein 1 Receptor Activity-Modifying Proteins Receptor, Angiotensin, Type 1/metabolism Receptors, Calcitonin/*metabolism Signal Transduction/drug effects
Publisher:Rockefeller University Press

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