[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Meyrath, Max; Luxembourg Institute of Health (LIH), Luxembourg.
Szpakowska, Martyna; Luxembourg Institute of Health (LIH), Luxembourg.
Zeiner, Julian; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Massotte, Laurent; Neurophysiology Unit, GIGA Neurosciences, University of Liège
Merz, Myriam P.; Luxembourg Institute of Health (LIH), Luxembourg.
Benkel, Tobias; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Simon, Katharina; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Ohnmacht, Jochen ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Turner, Jonathan ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) ; Luxembourg Institute of Health (LIH), Luxembourg.
Krüger, Rejko ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Seutin, Vincent; Neurophysiology Unit, GIGA Neurosciences, University of Liège
Ollert, Markus; Luxembourg Institute of Health (LIH), Luxembourg.
Kostenis, Evi; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
Chevigné, Andy ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) ; Luxembourg Institute of Health (LIH), Luxembourg.
