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On the existence of a possible A2A-D2-β- arrestin2 complex: A2A agonist modulation of D2 agonist-induced β-arrestin2 recruitment Borroto-Escuela, Dasiel O. Romero-Fernandez, Wilber Tarakanov, Alexander O. Ciruela, Francisco Agnati, Luigi F. Fuxe, Kjell Receptores de neurotransmisores Receptores Dopamina - Receptores Given that coactivation of adenosine A2A (A2AR) and dopamine D2 (D2R) receptors results in the coaggregation, cointernalization, and codesensitization of the A2AR and D 2R and the role of scaffolding protein β-arrestin2 in the desensitization, internalization, and signaling of G-protein-coupled receptors, in this study we explored the ability of the A2AR agonist CGS21680 in A2AR-D2R-coexpressing cells to modulate the D 2R agonist-induced recruitment of β-arrestin2 to the D 2R by means of proximity-based bioluminescence resonance energy transfer (BRET2) and co-trafficking analysis. We found evidence that CGS21680 can increase the maximal BRET2 signal between β-arrestin2RLuc and D2LRGFP2 upon D 2R activation, by increasing the potency of the D2R agonist to exert this action. In addition, this change was associated with an increased formation of cytoplasmic clusters containing β-arrestin2 GFP2 and D2LRYFP as seen from the co-trafficking analysis. Furthermore, the A2AR agonist advanced the time for the increase in Akt phosphorylation obtained with the D2R agonist. Finally, using a novel bioinformatics approach to predict the protein-protein interface, we have also found that amino acid pro-triplets TNY, LLS, RAF, and VSR may be crucial for the -induced β-arrestin2 recruitment by A2AR-D2R heteromers. Taken together, the results indicate that the antagonistic A2AR-D2R allosteric receptor-receptor interaction in A2AR-D2R heteromers favors β-arrestin2 recruitment to the D2LR protomer with subsequent cointernalization associated with a reduced time onset of Akt phosphorylation followed by a rapid dephosphorylation. Thus, β-arrestin2 action becomes more rapid and short-lasting and, in this way, mimics G-protein-mediated signaling. 2011-03-11 journal article Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Alexander O. Tarakanov, Francisco Ciruela, Luigi F. Agnati, Kjell Fuxe, On the Existence of a Possible A2A–D2–β-Arrestin2 Complex: A2A Agonist Modulation of D2 Agonist-Induced β-Arrestin2 Recruitment, Journal of Molecular Biology, Volume 406, Issue 5, 2011, Pages 687-699, ISSN 0022-2836, https://doi.org/10.1016/j.jmb.2011.01.022. (https://www.sciencedirect.com/science/article/pii/S0022283611000398) 0022-2836 https://hdl.handle.net/10630/45031 10.1016/j.jmb.2011.01.022 eng info:eu-repo/grantAgreement/Swedish_Research_Council//04X-715/SE/// info:eu-repo/grantAgreement/MICINN/SAF/SAF2008-01462/ES/// info:eu-repo/grantAgreement/MICINN/Consolider-Ingenio/CSD2008-00005/ES/// http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 International Sciencedirect