RT Journal Article SR Electronic T1 Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1–A2A Receptor Heteromers JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 2080 OP 2087 DO 10.1523/JNEUROSCI.3574-05.2006 VO 26 IS 7 A1 Ciruela, Francisco A1 Casadó, Vicent A1 Rodrigues, Ricardo J. A1 Luján, Rafael A1 Burgueño, Javier A1 Canals, Meritxell A1 Borycz, Janusz A1 Rebola, Nelson A1 Goldberg, Steven R. A1 Mallol, Josefa A1 Cortés, Antonio A1 Canela, Enric I. A1 López-Giménez, Juan F. A1 Milligan, Graeme A1 Lluis, Carme A1 Cunha, Rodrigo A. A1 Ferré, Sergi A1 Franco, Rafael YR 2006 UL http://www.jneurosci.org/content/26/7/2080.abstract AB The 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.