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Peptidase frees receptors in endosomes

The recycling (top, arrowheads) of CLR (red) back to the plasma membrane is blocked in cells lacking ECE-1 (bottom).

Internalized pain receptors are freed up by a peptidase for another round of agony, Padilla et al. reveal.

Peptidases on the cell surface cleave and thereby activate or inactivate small, extracellular peptides such as angiotensin. The enzymes also reside in internal compartments called endosomes, where their action is less apparent.

The new work shows that a peptidase called ECE-1 needs the low pH of the endosome to cleave several of its targets. One such peptide target was CGRP, which is released by cells during inflammation. Binding of CGRP to its receptor, CLR, induces pain signaling pathways in neurons. The peptide–receptor complex is then internalized into endosomes, which switches off the pain pathway.

Padilla and colleagues found that the internalized peptide/receptor was accompanied by ECE-1 into endosomes. There, the low pH encouraged the peptide to fall off its receptor. Cleavage by ECE-1 helped to ensure that the peptide did not rebind.

The dissolution of the pair released an associated scaffolding protein called β-arrestin, whose liberation allowed the receptor to return to the cell surface. This ECE-1–induced recycling was necessary for cells to respond to a second round of CGRP. Inhibitors of ECE-1, which were developed to block activation of a peptide that raises blood pressure, might thus have analgesic and antiinflammatory effects.

Reference:

Padilla, B.E., et al. 2007. J. Cell Biol. 179:981–997.[Abstract/Free Full Text]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 913K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?