Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors
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Sonja Hinz1, Gemma Navarro2,4, Dasiel Borroto-Escuela3, Benjamin F. Seibt1, York-Christoph Ammon1, Elisabetta de Filippo1, Azeem Danish1, Svenja K. Lacher1, Barbora Červinková1, Muhammad Rafehi1, Kjell Fuxe3, Anke C. Schiedel1, Rafael Franco2,4 and Christa E. Müller1
1PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
2Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
3Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
4Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Christa E. Müller, email: firstname.lastname@example.org
Keywords: adenosine receptors (ARs); G protein-coupled receptor (GPCR); immuno-oncology; pharmacology; receptor heteromerization
Received: November 08, 2017 Accepted: January 30, 2018 Published: February 06, 2018
The adenosine receptor (AR) subtypes A2A and A2B are rhodopsin-like Gs protein-coupled receptors whose expression is highly regulated under pathological, e.g. hypoxic, ischemic and inflammatory conditions. Both receptors play important roles in inflammatory and neurodegenerative diseases, are blocked by caffeine, and have now become major drug targets in immuno-oncology. By Förster resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), bimolecular fluorescence complementation (BiFC) and proximity ligation assays (PLA) we demonstrated A2A-A2BAR heteromeric complex formation. Moreover we observed a dramatically altered pharmacology of the A2AAR when co-expressed with the A2BAR (A2B ≥ A2A) in recombinant as well as in native cells. In the presence of A2BARs, A2A-selective ligands lost high affinity binding to A2AARs and displayed strongly reduced potency in cAMP accumulation and dynamic mass redistribution (DMR) assays. These results have major implications for the use of A2AAR ligands as drugs as they will fail to modulate the receptor in an A2A-A2B heteromer context. Accordingly, A2A-A2BAR heteromers represent novel pharmacological targets.
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