Ferré, SergiKarcz-Kubicha, MarzenaHope, Bruce T.Popoli, Patrizia P.Burgueño, JavierGutierrez, Angeles M.Casadó, VicentFuxe, KjellGoldberg, Steven R. GLluís i Biset, CarmeFranco Fernández, RafaelCiruela Alférez, Francisco2023-03-022023-03-0220020027-8424https://hdl.handle.net/2445/194443The physiological meaning of the coexpression of adenosine A2A receptors and group I metabotropic glutamate receptors in γ- aminobutyric acid (GABA)ergic striatal neurons is intriguing. Here we provide in vitro and in vivo evidence for a synergism between adenosine and glutamate based on subtype 5 metabotropic glutamate (mGluR5) and adenosine A2A (A2AR) receptor/receptor interactions. Colocalization of A2AR and mGluR5 at the membrane level was demonstrated in nonpermeabilized human embryonic kidney (HEK)-293 cells transiently cotransfected with both receptors by confocal laser microscopy. Complexes containing A2AR and mGluR5 were demonstrated by Western blotting of immunoprecipitates of either Flag-A2AR or hemagglutinin-mGluR5 in membrane preparations from cotransfected HEK-293 cells and of native A2AR and mGluR5 in rat striatal membrane preparations. In cotransfected HEK-293 cells a synergistic effect on extracellular signal-regulated kinase 1/2 phosphorylation and c-fos expression was demonstrated upon A2AR/mGluR5 costimulation. No synergistic effect was observed at the second messenger level (cAMP accumulation and intracellular calcium mobilization). Accordingly, a synergistic effect on c-fos expression in striatal sections and on counteracting phencyclidine-induced motor activation was also demonstrated after the central coadministration of A2AR and mGluR5 agonists to rats with intact dopaminergic innervation. The results suggest that a functional mGluR5/A2AR interaction is required to overcome the well-known strong tonic inhibitory effect of dopamine on striatal adenosine A2AR function.6 p.application/pdfeng(c) National Academy of Sciences, 2002AdenosinaAdeninaDopaminaNeurotransmissorsAdenosineAdenineDopamineNeurotransmittersinfo:eu-repo/semantics/article5025022023-03-02info:eu-repo/semantics/openAccess