Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers

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 A(1) receptors (A(1)Rs) and A(2A) receptors (A(2A)Rs) 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 A(1)R-A(2A)R heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A(1)R and A(2A)R 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 A(1)R-A(2A)R heteromer is the ability of A(2A)R activation to reduce the affinity of the A(1)R 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 A(1)R-A(2A)R heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A(1)R-A(2A)R heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.