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

Author:

Meyrath Max,Szpakowska MartynaORCID,Zeiner Julian,Massotte Laurent,Merz Myriam P.,Benkel TobiasORCID,Simon Katharina,Ohnmacht JochenORCID,Turner Jonathan D.ORCID,Krüger Rejko,Seutin Vincent,Ollert Markus,Kostenis EviORCID,Chevigné AndyORCID

Abstract

AbstractEndogenous 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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