TY - JOUR
T1 - Endothelin-converting enzyme 1 degrades neuropeptides in endosomes to control receptor recycling
AU - Roosterman, Dirk
AU - Cottrell, Graeme
AU - Padilla, Benjamin
AU - Muller, Laurent
AU - Eckman, Christopher
AU - Bunnett, Nigel
AU - Steinhoff, Martin
PY - 2007
Y1 - 2007
N2 - Neuropeptide signaling requires the presence of G protein-coupled
receptors (GPCRs) at the cell surface. Activated GPCRs interact with
B-arrestins, which mediate receptor desensitization, endocytosis,
and mitogenic signaling, and the peptide receptor arrestin complex
is sequestered into endosomes. Although dissociation of
B-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 B-arrestins
followed by trafficking of the SP NK1R B-arrestin complex to early
endosomes containing ECE-1d. ECE-1 degraded SP in acidified
endosomes, disrupting the complex; B-arrestins returned to the
cytosol, and the NK1R, freed from B-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 B-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.
AB - Neuropeptide signaling requires the presence of G protein-coupled
receptors (GPCRs) at the cell surface. Activated GPCRs interact with
B-arrestins, which mediate receptor desensitization, endocytosis,
and mitogenic signaling, and the peptide receptor arrestin complex
is sequestered into endosomes. Although dissociation of
B-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 B-arrestins
followed by trafficking of the SP NK1R B-arrestin complex to early
endosomes containing ECE-1d. ECE-1 degraded SP in acidified
endosomes, disrupting the complex; B-arrestins returned to the
cytosol, and the NK1R, freed from B-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 B-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.
U2 - 10.1073/pnas.0701910104
DO - 10.1073/pnas.0701910104
M3 - Article
VL - 104
SP - 11838
EP - 11843
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 28
ER -