title: Evidence for the heterotetrameric structure of the adenosine A2A-dopamine D2 receptor complex.
abstract: Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D1receptor (D1R)-dopamine D3receptor (D3R) and adenosine A2Areceptor (A2AR)-dopamine D2receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A2AR-D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing theex vivoexpression of A2AR-D2R heteromers. The ability of A2AR agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A2AR-D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain vcasadoanguera@gmail.com vcasado@ub.edu.
authors.forename: Verònica
authors.initials: V
authors.lastname: Casadó-Anguera
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, U.S.A.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, U.S.A.
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain Institute of Biomedicine of the University of Barcelona (IBUB), 08028 Barcelona, Spain vcasadoanguera@gmail.com vcasado@ub.edu.
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
mesh_terms: D000494:Allosteric Regulation; D019281:Dimerization; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2
keywords: G-protein-coupled receptor (GPCR); adenosine receptors; allosteric modulation; dopamine receptors; heteromerization; homodimerization