RT Journal Article
SR Electronic
T1 Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A<sub>1</sub>–A<sub>2A</sub> 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.