title: Modulation of GABA transport by adenosine A1R-A2AR heteromers, which are coupled to both Gs- and G(i/o)-proteins.
abstract: 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.
authors: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 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: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics; D019921:Biotinylation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D008954:Models, Biological; D009557:Nipecotic Acids / Q000494:pharmacology; D010660:Phenylisopropyladenosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D058905:Purinergic Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D018682:GABA Agents; D050485:GABA Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; D009557:Nipecotic Acids; D058905:Purinergic Agents; D043683:Receptors, Adenosine A2; D011994:Recombinant Proteins; C054562:yellow fluorescent protein, Bacteria; D014316:Tritium; D010660:Phenylisopropyladenosine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs