Published online
doi:10.1083/jcb.200704053
The Journal of Cell Biology, Vol. 179, No. 5, 981-997
The Rockefeller University Press, 0021-9525 $30.00
© Padilla et al.
Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and β-arrestins
Benjamin E. Padilla1,
Graeme S. Cottrell1,
Dirk Roosterman2,
Stella Pikios1,
Laurent Muller3,
Martin Steinhoff2, and
Nigel W. Bunnett1
1 Departments of Surgery and Physiology, University of California, San Francisco, San Francisco, CA 94143
2 Department of Dermatology, Interdisciplinary Center for Clinical Research, and the Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, 48149 Münster, Germany
3 INSERM U 36 College de France Paris, 75005 Paris, France
Correspondence to Nigel W. Bunnett: nigel.bunnett{at}ucsf.edu
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), β-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP. CGRP degradation promotes CLR/RAMP1 recycling and β-arrestin2 redistribution to the cytosol. ECE-1 inhibition or knockdown traps CLR/RAMP1 and β-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 B2 receptor, which transiently interacts with β-arrestins. We propose a mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/β-arrestin complex, freeing internalized receptors from β-arrestins and promoting recycling and resensitization.
Abbreviations used in this paper: AT, angiotensin; AT1AR, angiotensin type 1A receptor; B2R, bradykinin 2 receptor; BK, bradykinin; CGRP, calcitonin gene-related peptide; CLR, calcitonin receptor-like receptor; ECE-1, endothelin-converting enzyme-1; ET, endothelin; GPCR, G protein–coupled receptor; NEP, neprilysin; NK1R, neurokinin 1 receptor; RAMP1, receptor activity-modifying protein 1; rhECE-1, recombinant human ECE-1; SP, substance P; V2R, vasopressin 2 receptor.
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