title: Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer.
abstract: The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR-D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address: sferre@intra.nida.nih.gov.
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 2092, USA.
authors.forename: Dardo
authors.initials: D
authors.lastname: Tomasi
authors.affiliation: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.affiliation: Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 2092, USA.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D002110:Caffeine
keywords: Adenosine A2A receptor; Caffeine; Dopamine D2 receptor; Heteromer; Parkinson's disease; Striatum