Allosteric interactions between agonists and antagonists within the adenosine A₂A receptor-dopamine D₂ receptor heterotetramer
2015
Bonaventura, Jordi | Navarro, Gemma | Casadòó-Anguera, Verònica | Azdad, Karima | Rea, William | Moreno, Estefanòóía | Brugarolas, Marc | Mallol, Josefa | Canela, Enric I. | Lluòóíís, Carme | Cortòóííés, Antoni | Volkow, Nora D. | Schiffmann, Serge N. | Ferròóííéé, Sergi | Casadòóííééó, Vicent
Adenosine A ₂A receptor (A ₂AR)-dopamine D ₂ receptor (D ₂R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A ₂AR-D ₂R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D ₂R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A ₂AR agonists, but also A ₂AR antagonists, decrease the affinity and intrinsic efficacy of D ₂R agonists and the affinity of D ₂R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A ₂AR-D ₂R heteromers as heterotetramers, constituted by A ₂AR and D ₂R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A ₂AR antagonists behaved as A ₂AR agonists and decreased D ₂R function in the brain.
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