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 and Andy Chevigné ()
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Max Meyrath: Luxembourg Institute of Health (LIH), rue Henri Koch 29
Martyna Szpakowska: Luxembourg Institute of Health (LIH), rue Henri Koch 29
Julian Zeiner: University of Bonn, Nussallee 6
Laurent Massotte: University of Liège, avenue de l’hopital
Myriam P. Merz: Luxembourg Institute of Health (LIH), rue Henri Koch 29
Tobias Benkel: University of Bonn, Nussallee 6
Katharina Simon: University of Bonn, Nussallee 6
Jochen Ohnmacht: University of Luxembourg, avenue du Swing 6
Jonathan D. Turner: Luxembourg Institute of Health (LIH), rue Henri Koch 29
Rejko Krüger: University of Luxembourg, avenue du Swing 6
Vincent Seutin: University of Liège, avenue de l’hopital
Markus Ollert: Luxembourg Institute of Health (LIH), rue Henri Koch 29
Evi Kostenis: University of Bonn, Nussallee 6
Andy Chevigné: Luxembourg Institute of Health (LIH), rue Henri Koch 29

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16664-0

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