Untangling dopamine-adenosine receptor-receptor assembly in experimental parkinsonism in rats.
Parkinson's disease (PD) is a dopaminergic-related pathology in which functioning of the basal ganglia is altered. It has been postulated that a direct receptor-receptor interaction - i.e. of dopamine D2 receptor (D2R) with adenosine A2A receptor (A2AR) (forming D2R-A2AR oligomers) - finely regulates this brain area. Accordingly, elucidating whether the pathology prompts changes to these complexes could provide valuable information for the design of new PD therapies. Here, we first resolved a long-standing question concerning whether D2R-A2AR assembly occurs in native tissue: by means of different complementary experimental approaches (i.e. immunoelectron microscopy, proximity ligation assay and TR-FRET), we unambiguously identified native D2R-A2AR oligomers in rat striatum. Subsequently, we determined that, under pathological conditions (i.e. in a rat PD model), D2R-A2AR interaction was impaired. Collectively, these results provide definitive evidence for alteration of native D2R-A2AR oligomers in experimental parkinsonism, thus conferring the rationale for appropriate oligomer-based PD treatments.
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Víctor
V
Fernández-Dueñas
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Jaume J
JJ
Taura
Institut de Génomique Fonctionnelle, CNRS, UMR5203, Montpellier, France. INSERM, U.661, Montpellier and Université Montpellier 1,2, Montpellier, F-34094, France.
Martin
M
Cottet
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Maricel
M
Gómez-Soler
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Marc
M
López-Cano
IRIBHM, Université Libre de Bruxelles, B1070 Brussels, Belgium.
Catherine
C
Ledent
Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
Masahiko
M
Watanabe
Cisbio Bioassays, 30200 Codolet, France.
Eric
E
Trinquet
Institut de Génomique Fonctionnelle, CNRS, UMR5203, Montpellier, France. INSERM, U.661, Montpellier and Université Montpellier 1,2, Montpellier, F-34094, France.
Jean-Philippe
JP
Pin
Instituto de Investigación en Discapacidades Neurológicas (IDINE), Dept Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, 02006 Albacete, Spain.
Rafael
R
Luján
Institut de Génomique Fonctionnelle, CNRS, UMR5203, Montpellier, France. INSERM, U.661, Montpellier and Université Montpellier 1,2, Montpellier, F-34094, France. tdurroux@igf.cnrs.fr fciruela@ub.edu.
Thierry
T
Durroux
Unitat de Farmacologia, Departament Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain. tdurroux@igf.cnrs.fr fciruela@ub.edu.
Francisco
F
Ciruela
D000818:Animals; D001921:Brain / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000737:chemistry*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D016627:Oxidopamine / Q000737:chemistry; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000737:chemistry*; D018047:Receptors, Purinergic P1 / Q000737:chemistry*
D008024:Ligands; D011954:Receptors, Dopamine; D018047:Receptors, Purinergic P1; D016627:Oxidopamine; D004298:Dopamine
Immunoelectron microscopy; Oligomerization; Parkinson’s disease; Proximity ligation assay; TR-FRET