title: Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.
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.
authors.affiliation: Department 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;
authors.forename: Jordi
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: Department 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;
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Department 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;
authors.forename: Verònica
authors.initials: V
authors.lastname: Casadó-Anguera
authors.affiliation: Laboratory of Neurophysiology, Universite Libre de Bruxelles-Neuroscience Institute, 1070 Brussels, Belgium;
authors.forename: Karima
authors.initials: K
authors.lastname: Azdad
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224;
authors.forename: William
authors.initials: W
authors.lastname: Rea
authors.affiliation: Department 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;
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Department 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;
authors.forename: Marc
authors.initials: M
authors.lastname: Brugarolas
authors.affiliation: Department 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;
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.affiliation: Department 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;
authors.forename: Enric I
authors.initials: EI
authors.lastname: Canela
authors.affiliation: Department 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;
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Department 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;
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.affiliation: Laboratory of Neurophysiology, Universite Libre de Bruxelles-Neuroscience Institute, 1070 Brussels, Belgium;
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224; sferre@intra.nida.nih.gov vcasado@ub.edu.
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.affiliation: Department 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; sferre@intra.nida.nih.gov vcasado@ub.edu.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D060807:Bioluminescence Resonance Energy Transfer Techniques; D016466:CHO Cells; D003342:Corpus Striatum / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008297:Male; D018613:Microscopy, Confocal; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*; D012756:Sheep; D013997:Time Factors
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2
keywords: GPCR heteromers; adenosine A2A receptor; caffeine; dopamine D2 receptor