The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides

Max Meyrath, Martyna Szpakowska, Julian Zeiner, Laurent Massotte, Myriam P. Merz, Tobias Benkel, Katharina Simon, Jochen Ohnmacht, Jonathan D. Turner, Rejko Krüger, Vincent Seutin, Markus Ollert, Evi Kostenis, Andy Chevigné*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number3033
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Dec 2020

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