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Open AccessArticle

Adenosine A2A and A3 Receptors Are Able to Interact with Each Other. A Further Piece in the Puzzle of Adenosine Receptor-Mediated Signaling

1
Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain
2
Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, 33006 Asturias, Spain
3
Instituto de Neurociencias del Principado de Asturias (INEUROPA), 33006 Asturias, Spain
4
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33006 Asturias, Spain
5
Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
6
Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
7
School of Chemistry, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Current address: RG Neuroplasticity, Leibniz Institute for Neurobiology, 39118, Magdeburg, Germany.
Equal contribution.
Int. J. Mol. Sci. 2020, 21(14), 5070; https://doi.org/10.3390/ijms21145070
Received: 25 June 2020 / Revised: 10 July 2020 / Accepted: 13 July 2020 / Published: 17 July 2020
(This article belongs to the Special Issue Dissecting the Purinergic Signaling Puzzle)
The aim of this paper was to check the possible interaction of two of the four purinergic P1 receptors, the A2A and the A3. Discovery of the A2A–A3 receptor complex was achieved by means of immunocytochemistry and of bioluminescence resonance energy transfer. The functional properties and heteromer print identification were addressed by combining binding and signaling assays. The physiological role of the novel heteromer is to provide a differential signaling depending on the pre-coupling to signal transduction components and/or on the concentration of the endogenous agonist. The main feature was that the heteromeric context led to a marked decrease of the signaling originating at A3 receptors. Interestingly from a therapeutic point of view, A2A receptor antagonists overrode the blockade, thus allowing A3 receptor-mediated signaling. The A2A–A3 receptor heteromer print was detected in primary cortical neurons. These and previous results suggest that all four adenosine receptors may interact with each other. Therefore, each adenosine receptor could form heteromers with distinct properties, expanding the signaling outputs derived from the binding of adenosine to its cognate receptors. View Full-Text
Keywords: cross-antagonism; cortical neurons; heteromer print; purinergic P1 receptors; G-protein-coupled receptors cross-antagonism; cortical neurons; heteromer print; purinergic P1 receptors; G-protein-coupled receptors
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Lillo, A.; Martínez-Pinilla, E.; Reyes-Resina, I.; Navarro, G.; Franco, R. Adenosine A2A and A3 Receptors Are Able to Interact with Each Other. A Further Piece in the Puzzle of Adenosine Receptor-Mediated Signaling. Int. J. Mol. Sci. 2020, 21, 5070.

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