Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A ₁–A _2A Receptor Heteromers

Abstract

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 ₁Rs) and A _2A receptors (A _2ARs) 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 ₁R–A _2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A ₁R and A _2AR 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 ₁R–A _2AR heteromer is the ability of A _2AR activation to reduce the affinity of the A ₁R 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 ₁R–A _2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A ₁R–A _2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.