期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 406, 期 5, 页码 687-699出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.01.022
关键词
heteromerization; G-protein-coupled receptors; allosteric modulation; internalization; receptor-protein interaction
资金
- Swedish Research Council [04X-715]
- Torsten and Ragnar Soderberg Foundation
- Hjarnfonden and Marianne and Marcus Wallenberg Foundation
- Ministerio de Ciencia e Innovacion [SAF2008-01462, CSD2R008-00005]
Given that coactivation of adenosine A(2A) (A(2A)R) and dopamine D-2 (D2R) receptors results in the coaggregation, cointernalization, and codesensitization of the A(2A)R and D2R and the role of scaffolding protein beta-arrestin2 in the desensitization, internalization, and signaling of G-protein-coupled receptors, in this study we explored the ability of the A(2A)R agonist CGS21680 in A(2A)R-D2R-coexpressing cells to modulate the D2R agonist-induced recruitment of beta-arrestin2 to the D2R 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 beta-arrestin2(RLuc) and D2LRGFP2 upon D2R 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 beta-arrestin2(GFP2) and D2LRYFP as seen from the co-trafficking analysis. Furthermore, the A(2A)R 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 beta-arrestin2 recruitment by A(2A)R-D2R heteromers. Taken together, the results indicate that the antagonistic A(2A)R-D2R allosteric receptor receptor interaction in A(2A)R-D2R heteromers favors beta-arrestin2 recruitment to the D2LR protomer with subsequent cointernalization associated with a reduced time onset of Akt phosphorylation followed by a rapid dephosphorylation. Thus, beta-arrestin2 action becomes more rapid and short-lasting and, in this way, mimics G-protein-mediated signaling. (C) 2011 Elsevier Ltd. All rights reserved.
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