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The Journal of Neuroscience, February 15, 2006, 26(7):2080-2087; doi:10.1523/JNEUROSCI.3574-05.2006

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Cellular/Molecular
Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A₁–A_2A Receptor Heteromers

Francisco Ciruela,¹ Vicent Casadó,¹ Ricardo J. Rodrigues,² Rafael Luján,³ Javier Burgueño,⁴ Meritxell Canals,¹ Janusz Borycz,⁵ Nelson Rebola,² Steven R. Goldberg,⁵ Josefa Mallol,¹ Antonio Cortés,¹ Enric I. Canela,¹ Juan F. López-Giménez,⁶ Graeme Milligan,⁶ Carme Lluis,¹ Rodrigo A. Cunha,² Sergi Ferré,⁵ and Rafael Franco¹

¹Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain, ²Centre for Neuroscience of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal, ³Facultad de Medicina and Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, 02006 Albacete, Spain, ⁴Target Validation, Laboratoris Dr. Esteve, Parc Científic de Barcelona, 08028 Barcelona, Spain, ⁵Behavioral Neuroscience Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and ⁶Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Correspondence should be addressed to Sergi Ferré, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224. Email: sferre{at}intra.nida.nih.gov

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 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 A₁R–A_2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A₁R 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 A₁R–A_2AR heteromer is the ability of A_2AR 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–A_2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A₁R–A_2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.

Key words: adenosine A₁ receptor; adenosine A_2A receptor; heteromeric receptors; glutamate; striatum; caffeine

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Received Aug. 23, 2005; revised Jan. 9, 2005; accepted Jan. 10, 2006.

Correspondence should be addressed to Sergi Ferré, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224. Email: sferre{at}intra.nida.nih.gov

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