TY - JOUR
T1 - The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides
AU - Meyrath, Max
AU - Szpakowska, Martyna
AU - Zeiner, Julian
AU - Massotte, Laurent
AU - Merz, Myriam P.
AU - Benkel, Tobias
AU - Simon, Katharina
AU - Ohnmacht, Jochen
AU - Turner, Jonathan D.
AU - Krüger, Rejko
AU - Seutin, Vincent
AU - Ollert, Markus
AU - Kostenis, Evi
AU - Chevigné, Andy
N1 - Funding Information:
This study was supported by the Luxembourg Institute of Health (LIH) MESR (grants 20160116 and 20170113), Luxembourg National Research Fund (FNR) (INTER/FWO “Nanokine” - grant 15/10358798), Pathfinder “LIH383” (PF18/13255064), F.R.S.-FNRS-Télévie (grants 7456814 and 7461515). M. Meyrath and M. Merz are the Luxembourg FNR PhD fellows (grants AFR-3004509 and PRIDE-11012546 “Nex-tImmune”). T.B. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 214362475/GRK1873/2. E.K. was supported by the German research foundation (DFG)-funded research unit FOR2372 with the grants KO 1582/10-1 and -2. JO and RK were supported by the Luxembourg FNR (MaMaSyn and PEARL) and the Pelican Foundation. J.T. was supported by the Luxembourg FNR (C16/BM/11342695 “MetCOEPs”, and C12/BM/3985792 “Epi-Path”). The authors wish to thank Manuel Counson and Nadia Beaupain for their technical help, Oliver Hunewald for his support in database and phylogenetic analyses, Maria Konstantinou and the Luxembourg national cytometry platform for their help with ImageStream analysis, Julien Hanson for critical reading of the manuscript and Joanna Muz for her assistance for figure design.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3’s negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.
AB - Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3’s negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.
UR - http://www.scopus.com/inward/record.url?scp=85086661050&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/32561830
U2 - 10.1038/s41467-020-16664-0
DO - 10.1038/s41467-020-16664-0
M3 - Article
C2 - 32561830
AN - SCOPUS:85086661050
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3033
ER -