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Purinergic Signal. 2013 Sep;9(3):433-49. doi: 10.1007/s11302-013-9364-5. Epub 2013 May 10.

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

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Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Av. Professor Egas Moniz, Edificio Egas Moniz, 1649-028, Lisbon, Portugal.


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.

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