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Adenosine A2A-Dopamine D2 Receptor-Receptor Heteromerization

Adenosine A2A-Dopamine D2 Receptor-Receptor Heteromerization
There is evidence for strong functional antagonistic interactions between adenosine A2A receptors (A2ARs) and dopamine D2 receptors (D2Rs). Although a close physical interaction between both receptors has recently been shown using co-immunoprecipitation and co-localization assays, the existence of a A2AR-D2R protein-protein interaction still had to be demonstrated in intact living cells. In the present work, fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) techniques were used to confirm the occurrence of A2AR-D2R interactions in co-transfected cells. The degree of A2AR-D2R heteromerization, measured by BRET, did not vary after receptor activation with selective agonists, alone or in combination. BRET competition experiments were performed using a chimeric D2R-D1R in which helices 5 and 6, the third intracellular loop (I3), and the third extracellular loop (E3) of the D2R were replaced by those of the dopamine D1 receptor (D1R). Although the wild type D2R was able to decrease the BRET signal, the chimera failed to achieve any effect. This suggests that the helix 5-I3-helix 6-E3 portion of D2R holds the site(s) for interaction with A2AR. Modeling of A2AR and D2R using a modified rhodopsin template followed by molecular dynamics and docking simulations gave essentially two different possible modes of interaction between D2R and A2AR. In the most probable one, helix 5 and/or helix 6 and the N-terminal portion of I3 from D2R approached helix 4 and the C-terminal portion of the C-tail from the A2AR, respectively.
- United States Department of the Interior United States
- University of Montreal Canada
- Dulbecco Telethon Institute Italy
- National Institute on Drug Abuse United States
- United States Department of the Interior United States
Models, Molecular, Adenosine, Receptor, Adenosine A2A, Dopamine, Recombinant Fusion Proteins, Adenosina, Dopamina, Transfection, Fluorescence, Cell Line, GPCRs; molecular recognition; protein-protein docking, Humans, Computer Simulation, Binding Sites, Receptors, Dopamine D2, Metabolisme, Transferència d'energia, Metabolism, Energy Transfer, Energy transfer, Luminescent Measurements, Dimerization, Protein Binding
Models, Molecular, Adenosine, Receptor, Adenosine A2A, Dopamine, Recombinant Fusion Proteins, Adenosina, Dopamina, Transfection, Fluorescence, Cell Line, GPCRs; molecular recognition; protein-protein docking, Humans, Computer Simulation, Binding Sites, Receptors, Dopamine D2, Metabolisme, Transferència d'energia, Metabolism, Energy Transfer, Energy transfer, Luminescent Measurements, Dimerization, Protein Binding
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citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).421 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1% visibility views 164 download downloads 179 - 164views179downloads
Data source Views Downloads IRIS UNIMORE - Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia 83 100 Diposit Digital de la Universitat de Barcelona 81 79


