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

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 B2 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/ - arrestin complex, freeing internalized receptors from beta- arrestins and promoting recycling and resensitization.