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 D1 receptor (D1R)–dopamine D3 receptor (D3R) and adenosine A2A receptor (A2AR)–dopamine D2 receptor (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 the ex vivo expression 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.
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April 2016
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Cover Image
Endoplasmic reticulumendosome contact sites. This pseudo-colored electron microscopy image shows the formation of inter-organelle membrane contact sites between late endosomes (magenta) and the endoplasmic reticulum (ER; green). This tethering results from the interaction between two ER-anchored proteins (VAP-A and VAP-B) and the late endosomeanchored protein STARD3NL. Mitochondria: brown; nucleus: blue. For further details see pp. 493-498. Image kindly provided by Fabien Alpy. - PDF Icon PDF LinkTable of Contents
Review Article|
April 11 2016
Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex
Verònica Casadó-Anguera;
Verònica Casadó-Anguera
1
*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
1Correspondence may be addressed to either of these authors (email vcasadoanguera@gmail.com or vcasado@ub.edu).
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Jordi Bonaventura;
Jordi Bonaventura
†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.
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Estefanía Moreno;
Estefanía Moreno
*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
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Gemma Navarro;
Gemma Navarro
*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
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Antoni Cortés;
Antoni Cortés
*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
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Sergi Ferré;
Sergi Ferré
§Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, U.S.A.
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Vicent Casadó
Vicent Casadó
1
*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
1Correspondence may be addressed to either of these authors (email vcasadoanguera@gmail.com or vcasado@ub.edu).
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Publisher: Portland Press Ltd
Received:
February 04 2016
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2016 Authors; published by Portland Press Limited
2016
Biochem Soc Trans (2016) 44 (2): 595–600.
Article history
Received:
February 04 2016
Citation
Verònica Casadó-Anguera, Jordi Bonaventura, Estefanía Moreno, Gemma Navarro, Antoni Cortés, Sergi Ferré, Vicent Casadó; Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex. Biochem Soc Trans 15 April 2016; 44 (2): 595–600. doi: https://doi.org/10.1042/BST20150276
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