Dopamine D2 receptor-mediated modulation of adenosine A2A receptor agonist binding within the A2AR/D2R oligomer framework |
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Authors: | Ví ctor Ferná ndez-Dueñ as,Maricel Gó mez-Soler,Xavier Morató ,Fabiana Nú ñ ez,Arijit Das,T. Santhosh Kumar,Serge Jaumà ,Kenneth A. Jacobson,Francisco Ciruela |
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Affiliation: | 1. Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, 08907 Barcelona, Spain;2. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 20892 Bethesda, USA;3. Movement Disorders Unit, Neurology Service, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, 08907 Barcelona, Spain |
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Abstract: | The molecular interaction between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine–dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson’s disease). While the effects of A2AR challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D2R-mediated allosteric modulation of A2AR binding when an A2AR/D2R oligomer is established. Thus, we synthesized fluorescent A2AR agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A2AR binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A2AR agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A2AR agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D2Rs to modulate A2AR binding, thus serving to facilitate the preliminary selection of D2R-like candidate drugs in the management of Parkinson’s disease. |
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Keywords: | A2AR D2R Parkinson&rsquo s disease Receptor&ndash receptor allosterism Antiparkinsonian drugs |
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