Research Papers:

Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors

Sonja Hinz, Gemma Navarro, Dasiel Borroto-Escuela, Benjamin F. Seibt, York-Christoph Ammon, Elisabetta de Filippo, Azeem Danish, Svenja K. Lacher, Barbora Červinková, Muhammad Rafehi, Kjell Fuxe, Anke C. Schiedel, Rafael Franco and Christa E. Müller _

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Oncotarget. 2018; 9:13593-13611. https://doi.org/10.18632/oncotarget.24423

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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

Correspondence to:

Christa E. Müller, email: [email protected]

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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