Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor
Jordi Bonaventura1, Gemma Navarro2, Verònica Casadó-Anguera2
1Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, and Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain; Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224;
Abstract:
Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) 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 A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.
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