A1R-A2AR heteromers coupled to Gs and G i/0 proteins modulate GABA transport into astrocytes

• Published in: Purinergic signalling Vol. 9; no. 3; pp. 433 - 449
• 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: Netherlands 01.09.2013
• Subjects: Adenosine - metabolism; Animals; Astrocytes - metabolism; Blotting, Western; Female; GABA Plasma Membrane Transport Proteins - metabolism; gamma-Aminobutyric Acid - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gs - metabolism; HEK293 Cells; Humans; Immunohistochemistry; Male; Radioligand Assay; Rats; Rats, Wistar; Receptor, Adenosine A1 - metabolism; Receptor, Adenosine A2A - metabolism; Synaptic Transmission - physiology; Transfection
• ISSN: 1573-9546
• DOI: 10.1007/s11302-013-9364-5

Astrocytes play a key role in modulating synaptic transmission by controlling extracellular gamma-aminobutyric acid (GABA) levels via GAT-1 and GAT-3 GABA transporters (GATs). Using primary cultures of rat astrocytes, we show here that a further level of regulation of GABA uptake occurs via modulation of the GATs by the adenosine A1 (A1R) and A2A (A2AR) receptors. This regulation occurs through A1R-A2AR heteromers that signal via two different G proteins, Gs and Gi/0, and either enhances (A2AR) or inhibits (A1R) GABA uptake. These results provide novel mechanistic insight into how GPCR heteromers signal. Furthermore, we uncover a previously unknown mechanism where 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.