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

[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 Marc Roger ; Université de Liège - ULiège > FARAH

Szpakowska, Martyna

Zeiner, Julian

Massotte, Laurent

Merz, Myriam P.

Benkel, Tobias

Simon, Katharina

Ohnmacht, Jochen

Turner, Jonathan D.

Krüger, Rejko

More authors (4 more)

Language :

English

Title :

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

Publication date :

19 June 2020

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Volume :

Issue :

Pages :

3033

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://pubmed.ncbi.nlm.nih.gov/32561830/

Available on ORBi :

since 25 June 2020

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Bibliography

Akil, H. et al. Endogenous opioids: overview and current issues. Drug Alcohol Depend. 51, 127–140 (1998).
Henderson, G. & McKnight, A. T. The orphan opioid receptor and its endogenous ligand-nociceptin/orphanin FQ. Trends Pharm. Sci. 18, 293–300 (1997).
Janecka, A., Fichna, J. & Janecki, T. Opioid receptors and their ligands. Curr. Top. Med. Chem. 4, 1–17 (2004).
Le Merrer, J., Becker, J. A., Befort, K. & Kieffer, B. L. Reward processing by the opioid system in the brain. Physiol. Rev. 89, 1379–1412 (2009).
Stein, C. & Machelska, H. Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharm. Rev. 63, 860–881 (2011).
Connor, M. & Christie, M. D. Opioid receptor signalling mechanisms. Clin. Exp. Pharm. Physiol. 26, 493–499 (1999).
Al-Hasani, R. & Bruchas, M. R. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115, 1363–1381 (2011).
Violin, J. D. & Lefkowitz, R. J. Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharm. Sci. 28, 416–422 (2007).
Bohn, L. M., Gainetdinov, R. R., Lin, F. T., Lefkowitz, R. J. & Caron, M. G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723 (2000).
Porter-Stransky, K. A. & Weinshenker, D. Arresting the development of addiction: the role of beta-arrestin 2 in drug abuse. J. Pharm. Exp. Ther. 361, 341–348 (2017).
Melik Parsadaniantz, S., Rivat, C., Rostene, W. & Reaux-Le Goazigo, A. Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat. Rev. Neurosci. 16, 69–78 (2015).
Szabo, I. et al. Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc. Natl Acad. Sci. USA 99, 10276–10281 (2002).
Pello, O. M. et al. Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur. J. Immunol. 38, 537–549 (2008).
Rossi, D. & Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol. 18, 217–242 (2000).
Murdoch, C. & Finn, A. Chemokine receptors and their role in inflammation and infectious diseases. Blood 95, 3032–3043 (2000).
Zlotnik, A. & Yoshie, O. The chemokine superfamily revisited. Immunity 36, 705–716 (2012).
Bachelerie, F. et al. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharm. Rev. 66, 1–79 (2014).
Bachelerie, F. et al. New nomenclature for atypical chemokine receptors. Nat. Immunol. 15, 207–208 (2014).
Graham, G. J., Locati, M., Mantovani, A., Rot, A. & Thelen, M. The biochemistry and biology of the atypical chemokine receptors. Immunol. Lett. 145, 30–38 (2012).
Nibbs, R. J. & Graham, G. J. Immune regulation by atypical chemokine receptors. Nat. Rev. Immunol. 13, 815–829 (2013).
Berahovich, R. D. et al. Endothelial expression of CXCR7 and the regulation of systemic CXCL12 levels. Immunology 141, 111–122 (2014).
Shimizu, S., Brown, M., Sengupta, R., Penfold, M. E. & Meucci, O. CXCR7 protein expression in human adult brain and differentiated neurons. PLoS ONE 6, e20680 (2011).
Regard, J. B., Sato, I. T. & Coughlin, S. R. Anatomical profiling of G protein-coupled receptor expression. Cell 135, 561–571 (2008).
Quinn, K. E., Mackie, D. I. & Caron, K. M. Emerging roles of atypical chemokine receptor 3 (ACKR3) in normal development and physiology. Cytokine 109, 17–23 (2018).
Koenen, J., Bachelerie, F., Balabanian, K., Schlecht-Louf, G., & Gallego, C. Atypical chemokine receptor 3 (ACKR3): a comprehensive overview of its expression and potential roles in the immune system. Mol. Pharmacol, 96, 809–818 (2019).
Rajagopal, S. et al. Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc. Natl Acad. Sci. USA 107, 628–632 (2010).
Heuninck, J. et al. Context-dependent signaling of CXC chemokine receptor 4 and atypical chemokine receptor 3. Mol. Pharm. 96, 778–793 (2019).
Odemis, V. et al. The presumed atypical chemokine receptor CXCR7 signals through G(i/o) proteins in primary rodent astrocytes and human glioma cells. Glia 60, 372–381 (2012).
Wang, C., Chen, W. & Shen, J. CXCR7 targeting and its major disease relevance. Front Pharm. 9, 641 (2018).
Burns, J. M. et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J. Exp. Med. 203, 2201–2213 (2006).
Szpakowska, M. et al. Human herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7. Biochem. Pharm. 114, 14–21 (2016).
Klein, K. R. et al. Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev. Cell 30, 528–540 (2014).
Alampour-Rajabi, S. et al. MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J. 29, 4497–4511 (2015).
Ikeda, Y., Kumagai, H., Skach, A., Sato, M. & Yanagisawa, M. Modulation of circadian glucocorticoid oscillation via adrenal opioid-CXCR7 signaling alters emotional behavior. Cell 155, 1323–1336 (2013).
Szpakowska, M. et al. Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists. Biochem. Pharm. 153, 299–309 (2018).
Szpakowska, M. et al. Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3. Br. J. Pharm. 175, 1419–1438 (2018).
Walker, J. M., Moises, H. C., Coy, D. H., Baldrighi, G. & Akil, H. Nonopiate effects of dynorphin and des-Tyr-dynorphin. Science 218, 1136–1138 (1982).
Gac, L., Butterick, T. A., Duffy, C. M., Teske, J. A. & Perez-Leighton, C. E. Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A. Peptides 76, 14–18 (2016).
Mansour, A., Hoversten, M. T., Taylor, L. P., Watson, S. J. & Akil, H. The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res 700, 89–98 (1995).
Zhang, J. et al. Role for G protein-coupled receptor kinase in agonist-specific regulation of mu-opioid receptor responsiveness. Proc. Natl Acad. Sci. USA 95, 7157–7162 (1998).
Adlere, I. et al. Modulators of CXCR4 and CXCR7/ACKR3 Function. Mol. Pharm. 96, 737–752 (2019).
Fang, Y., Ferrie, A. M., Fontaine, N. H., Mauro, J. & Balakrishnan, J. Resonant waveguide grating biosensor for living cell sensing. Biophys. J. 91, 1925–1940 (2006).
Schroder, R. et al. Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat. Biotechnol. 28, 943–949 (2010).
Grundmann, M. et al. Lack of beta-arrestin signaling in the absence of active G proteins. Nat. Commun. 9, 341 (2018).
Boldajipour, B. et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 132, 463–473 (2008).
Luker, K. E., Steele, J. M., Mihalko, L. A., Ray, P. & Luker, G. D. Constitutive and chemokine-dependent internalization and recycling of CXCR7 in breast cancer cells to degrade chemokine ligands. Oncogene 29, 4599–4610 (2010).
Saaber, F. et al. ACKR3 regulation of neuronal migration requires ACKR3 phosphorylation, but not beta-arrestin. Cell Rep. 26, 1473–1488 (2019).
Doijen, J. et al. Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements. PLoS ONE 12, e0185354 (2017).
Proost, P. et al. Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration. Blood 110, 37–44 (2007).
Naumann, U. et al. CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS ONE 5, e9175 (2010).
Canals, M. et al. Ubiquitination of CXCR7 controls receptor trafficking. PLoS ONE 7, e34192 (2012).
Banisadr, G., Podojil, J. R., Miller, S. D. & Miller, R. J. Pattern of CXCR7 gene expression in mouse brain under normal and inflammatory conditions. J. Neuroimmune Pharm. 11, 26–35 (2016).
Reinhardt, P. et al. Derivation and expansion using only small molecules of human neural progenitors for neurodegenerative disease modeling. PLoS ONE 8, e59252 (2013).
Mansour, A., Fox, C. A., Akil, H. & Watson, S. J. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci. 18, 22–29 (1995).
Lansu, K. et al. In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat. Chem. Biol. 13, 529–536 (2017).
Scimemi, A. & Beato, M. Determining the neurotransmitter concentration profile at active synapses. Mol. Neurobiol. 40, 289–306 (2009).
Guyon, A. et al. Enkephalin degradation in mouse brain studied by a new H.P.L.C. method: further evidence for the involvement of carboxydipeptidase. Life Sci. 25, 1605–1611 (1979).
de la Baume, S. et al. Selective participation of both “enkephalinase” and aminopeptidase activities in the metabolism of endogenous enkephalins. Life Sci. 31, 1753–1756 (1982).
Turner, A. J., Matsas, R. & Kenny, A. J. Are there neuropeptide-specific peptidases? Biochem. Pharm. 34, 1347–1356 (1985).
Gutkind, J. S. & Kostenis, E. Arrestins as rheostats of GPCR signalling. Nat. Rev. Mol. Cell Biol. 19, 615–616 (2018).
O’Hayre, M. et al. Genetic evidence that beta-arrestins are dispensable for the initiation of beta2-adrenergic receptor signaling to ERK. Sci Signal 10, eaal3395 (2017).
Tan-No, K. et al. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-D-aspartate receptor mechanism. Brain Res. 952, 7–14 (2002).
Lai, J. et al. Dynorphin A activates bradykinin receptors to maintain neuropathic pain. Nat. Neurosci. 9, 1534–1540 (2006).
Kuzmin, A., Madjid, N., Terenius, L., Ogren, S. O. & Bakalkin, G. Big dynorphin, a prodynorphin-derived peptide produces NMDA receptor-mediated effects on memory, anxiolytic-like and locomotor behavior in mice. Neuropsychopharmacology 31, 1928–1937 (2006).
Zagon, I. S., Goodman, S. R. & McLaughlin, P. J. Characterization of zeta (zeta): a new opioid receptor involved in growth. Brain Res. 482, 297–305 (1989).
Wuster, M., Schulz, R. & Herz, A. Specificity of opioids towards the mu-, delta- and epsilon-opiate receptors. Neurosci. Lett. 15, 193–198 (1979).
Grevel, J. & Sadee, W. An opiate binding site in the rat brain is highly selective for 4,5-epoxymorphinans. Science 221, 1198–1201 (1983).
Wollemann, M. & Benyhe, S. Non-opioid actions of opioid peptides. Life Sci. 75, 257–270 (2004).
Yarygin, K. N., Zhang, X. H. & Lee, N. M. Non-opioid dynorphin binding site on secretory vesicles of a pituitary-derived cell line. Brain Res. 791, 99–107 (1998).
Yaksh, T. L. et al. Mast cell degranulation and fibroblast activation in the morphine-induced spinal mass: role of mas-related G protein-coupled receptor signaling. Anesthesiology 131, 132–147 (2019).
Navines-Ferrer, A. et al. MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Sci. Rep. 8, 11628 (2018).
Koehl, A. et al. Structure of the micro-opioid receptor-Gi protein complex. Nature 558, 547–552 (2018).
Nomiyama, H. & Yoshie, O. Functional roles of evolutionary conserved motifs and residues in vertebrate chemokine receptors. J. Leukoc. Biol. 97, 39–47 (2015).
Szpakowska, M., Perez Bercoff, D. & Chevigne, A. Closing the ring: a fourth extracellular loop in chemokine receptors. Sci. Signal 7, pe21 (2014).
Szpakowska, M. et al. Function, diversity and therapeutic potential of the N-terminal domain of human chemokine receptors. Biochem. Pharm. 84, 1366–1380 (2012).
Nomiyama, H., Osada, N. & Yoshie, O. A family tree of vertebrate chemokine receptors for a unified nomenclature. Dev. Comp. Immunol. 35, 705–715 (2011).
Gustavsson, M. et al. Structural basis of ligand interaction with atypical chemokine receptor 3. Nat. Commun. 8, 14135 (2017).
Chatterjee, M. et al. Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis. 6, e1989 (2015).
Hartmann, T. N. et al. A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J. Leukoc. Biol. 84, 1130–1140 (2008).
Labuz, D. et al. Immune cell-derived opioids protect against neuropathic pain in mice. J. Clin. Invest. 119, 278–286 (2009).
Cabot, P. J., Carter, L., Schafer, M. & Stein, C. Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain. Pain 93, 207–212 (2001).
Schafer, M., Carter, L. & Stein, C. Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proc. Natl Acad. Sci. USA 91, 4219–4223 (1994).
Rogers, T. J., Steele, A. D., Howard, O. M. & Oppenheim, J. J. Bidirectional heterologous desensitization of opioid and chemokine receptors. Ann. N. Y Acad. Sci. 917, 19–28 (2000).
Grimm, M. C. et al. Opiate inhibition of chemokine-induced chemotaxis. Ann. N. Y Acad. Sci. 840, 9–20 (1998).
Levoye, A., Balabanian, K., Baleux, F., Bachelerie, F. & Lagane, B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood 113, 6085–6093 (2009).
Cornil, C. A., Balthazart, J., Motte, P., Massotte, L. & Seutin, V. Dopamine activates noradrenergic receptors in the preoptic area. J. Neurosci. 22, 9320–9330 (2002).
Bjorndal, A. et al. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J. Virol. 71, 7478–7487 (1997).
Ponten, J. & Macintyre, E. H. Long term culture of normal and neoplastic human glia. Acta Pathol. Microbiol Scand. 74, 465–486 (1968).
Schondorf, D. C. et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 5, 4028 (2014).
Dixon, A. S. et al. NanoLuc complementation reporter optimized for accurate measurement of protein interactions in cells. ACS Chem. Biol. 11, 400–408 (2016).
Carpenter, B., Nehme, R., Warne, T., Leslie, A. G. & Tate, C. G. Structure of the adenosine A(2A) receptor bound to an engineered G protein. Nature 536, 104–107 (2016).
Wan, Q. et al. Mini G protein probes for active G protein-coupled receptors (GPCRs) in live cells. J. Biol. Chem. 293, 7466–7473 (2018).
Laschet, C., Dupuis, N. & Hanson, J. A dynamic and screening-compatible nanoluciferase-based complementation assay enables profiling of individual GPCR-G protein interactions. J. Biol. Chem. 294, 4079–4090 (2019).
Schroder, R. et al. Applying label-free dynamic mass redistribution technology to frame signaling of G protein-coupled receptors noninvasively in living cells. Nat. Protoc. 6, 1748–1760 (2011).
Simon, K. et al. The orphan G protein-coupled receptor GPR17 negatively regulates oligodendrocyte differentiation via galphai/o and its downstream effector molecules. J. Biol. Chem. 291, 705–718 (2016).
Krebs, K. M. et al. Label-free whole cell biosensing for high-throughput discovery of activators and inhibitors targeting G protein-activated inwardly rectifying potassium channels. ACS Omega 3, 14814–14823 (2018).
Malfacini, D. et al. Rational design of a heterotrimeric G protein alpha subunit with artificial inhibitor sensitivity. J. Biol. Chem. 294, 5747–5758 (2019).
Seutin, V., Verbanck, P., Massotte, L. & Dresse, A. Galanin decreases the activity of locus coeruleus neurons in vitro. Eur. J. Pharm. 164, 373–376 (1989).
Cao-Lei, L. et al. Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain. J. Psychiatr. Res. 47, 1597–1607 (2013).
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25, 402–408 (2001).
Miller, J. A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014).
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621–628 (2008).