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

      The Journal of neuroscience : the official journal of the Society for Neuroscience

      Transfection, physiology, drug effects, Synaptic Transmission, metabolism, Recombinant Proteins, genetics, Receptors, Adenosine A2, Receptor, Adenosine A1, Rats, Sprague-Dawley, Rats, Presynaptic Terminals, Male, Humans, Dimerization, Corpus Striatum, Cell Line, pharmacology, Caffeine, Animals

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          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 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.

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          Author and article information

          Journal
          10.1523/JNEUROSCI.3574-05.2006
          16481441

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