Modulation of GABA Transport by Adenosine A 1 R–A 2A R Heteromers, Which Are Coupled to Both G s - and G i/o -Proteins

• Published in: The Journal of neuroscience Vol. 31; no. 44; pp. 15629 - 15639
• 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: 02.11.2011
• ISSN: 0270-6474; 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.