Allosteric interactions between agonists and antagonists within the adenosine A2A receptordopamine D2 receptor heterotetramer

Abstract

Adenosine A2A receptor (A2A R)-dopamine D2 receptor (D2 R) 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 A2A R-D2 R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2 R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2A R agonists, but also A2A R antagonists, decrease the affinity and intrinsic efficacy of D2 R agonists and the affinity of D2 R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers AA2R-D 2 R heteromers as heterotetramers, constituted by A2A R and D2 R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2A R antagonists behaved as AA2R agonists and decreased D2R function in the brain.