Modulation of GABA transport by adenosine A1R-A2AR heteromers, which are coupled to both Gs- and G(i/o)-proteins

• Published in: The Journal of neuroscience Vol. 31; no. 44; p. 15629
• Main Authors: Cristóvão-Ferreira, Sofia, Navarro, Gemma, Brugarolas, Marc, Pérez-Capote, Kamil, Vaz, Sandra H, Fattorini, Giorgia, Conti, Fiorenzo, Lluis, Carmen, Ribeiro, Joaquim A, McCormick, Peter J, Casadó, Vicent, Franco, Rafael, Sebastião, Ana M
• Format: Journal Article
• Language: English
• Published: United States 02.11.2011
• Subjects: Analysis of Variance; Animals; Animals, Newborn; Astrocytes - drug effects; Astrocytes - metabolism; Bacterial Proteins - genetics; Biotinylation; Cells, Cultured; Cerebral Cortex - cytology; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; GABA Agents - pharmacology; GABA Plasma Membrane Transport Proteins - genetics; GABA Plasma Membrane Transport Proteins - metabolism; gamma-Aminobutyric Acid - metabolism; Gene Expression Regulation - drug effects; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics; Humans; Luminescent Proteins - genetics; Models, Biological; Nipecotic Acids - pharmacology; Phenylisopropyladenosine - metabolism; Protein Binding - drug effects; Purinergic Agents - pharmacology; Rats; Rats, Wistar; Receptors, Adenosine A2 - genetics; Receptors, Adenosine A2 - metabolism; Recombinant Proteins - metabolism; Time Factors; Transfection - methods; Tritium - metabolism
• ISSN: 1529-2401
• DOI: 10.1523/JNEUROSCI.2526-11.2011

Astrocytes play a key role in modulating synaptic transmission by controlling the available extracellular GABA via the GAT-1 and GAT-3 GABA transporters (GATs). Using primary cultures of rat astrocytes, we show here that an additional level of regulation of GABA uptake occurs via modulation of the GATs by the adenosine A(1) (A(1)R) and A(2A) (A(2A)R) receptors. This regulation occurs through a complex of heterotetramers (two interacting homodimers) of A(1)R-A(2A)R that signal via two different G-proteins, G(s) and G(i/o), and either enhances (A(2A)R) or inhibits (A(1)R) GABA uptake. These results provide novel mechanistic insight into how G-protein-coupled receptor heteromers signal. Furthermore, we uncover a previously unknown mechanism in which adenosine, in a concentration-dependent manner, acts via a heterocomplex of adenosine receptors in astrocytes to significantly contribute to neurotransmission at the tripartite (neuron-glia-neuron) synapse.