title: A1R-A2AR heteromers coupled to Gs and G i/0 proteins modulate GABA transport into astrocytes.
abstract: 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.
authors: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Av. Professor Egas Moniz, Edificio Egas Moniz, 1649-028, Lisbon, Portugal.
authors: Sofia
authors: S
authors: Cristóvão-Ferreira
authors: Gemma
authors: G
authors: Navarro
authors: Marc
authors: M
authors: Brugarolas
authors: Kamil
authors: K
authors: Pérez-Capote
authors: Sandra H
authors: SH
authors: Vaz
authors: Giorgia
authors: G
authors: Fattorini
authors: Fiorenzo
authors: F
authors: Conti
authors: Carmen
authors: C
authors: Lluis
authors: Joaquim A
authors: JA
authors: Ribeiro
authors: Peter J
authors: PJ
authors: McCormick
authors: Vicent
authors: V
authors: Casadó
authors: Rafael
authors: R
authors: Franco
authors: Ana M
authors: AM
authors: Sebastião
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D005680:gamma-Aminobutyric Acid; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D000241:Adenosine
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