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 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.
Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain.
Francisco
F
Ciruela
Vicent
V
Casadó
Ricardo J
RJ
Rodrigues
Rafael
R
Luján
Javier
J
Burgueño
Meritxell
M
Canals
Janusz
J
Borycz
Nelson
N
Rebola
Steven R
SR
Goldberg
Josefa
J
Mallol
Antonio
A
Cortés
Enric I
EI
Canela
Juan F
JF
López-Giménez
Graeme
G
Milligan
Carme
C
Lluis
Rodrigo A
RA
Cunha
Sergi
S
Ferré
Rafael
R
Franco
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002460:Cell Line; D003342:Corpus Striatum / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D008297:Male; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D043682:Receptor, Adenosine A1; D043683:Receptors, Adenosine A2; D011994:Recombinant Proteins; D002110:Caffeine