Ciruela Alférez, FranciscoCasadó, VicentRodrigues Sepúlveda Marques, Ricardo JorgeLuján, RafaelBurgueño, JavierCanals Buj, MeritxellBorycz, JanuszRebola, NelsonGoldberg, Steven R.Mallol Montero, JosefaCortés Tejedor, AntonioCanela Campos, Enric I. (Enric Isidre), 1949-López-Giménez, Juan F.Milligan, GraemeLluís i Biset, CarmeCunha, Rodrigo A.Ferré, SergiFranco Fernández, Rafael2018-05-152018-05-152006-02-150270-6474https://hdl.handle.net/2445/122382The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.8 p.application/pdfengcc-by-nc-sa (c) Ciruela Alférez, Francisco et al., 2006http://creativecommons.org/licenses/by-nc-sa/3.0/esAdenosinaNeurotransmissorsAdenosineNeurotransmittersinfo:eu-repo/semantics/article5340262018-05-15info:eu-repo/semantics/openAccess16481441