A 1 R–A 2A R heteromers coupled to G s and G i/0 proteins modulate GABA transport into astrocytes

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 A 1 (A 1 R) and A 2A (A 2A R) receptors. This regulation occurs through A 1 R–A 2A R heteromers that signal via two different G proteins, G s and G i/0 , and either enhances (A 2A R) or inhibits (A 1 R) 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.