Modulation of GABA transport by adenosine A1R-A2AR heteromers, which are coupled to both Gs- and G(i/o)-proteins

Sofia Cristóvão-Ferreira; Gemma Navarro; Marc Brugarolas; Kamil Pérez-Capote; Sandra H Vaz; Giorgia Fattorini; Fiorenzo Conti; Carmen Lluis; Joaquim A Ribeiro; Peter J McCormick; Vicent Casadó; Rafael Franco; Ana M Sebastião

doi:10.1523/JNEUROSCI.2526-11.2011

Modulation of GABA transport by adenosine A1R-A2AR heteromers, which are coupled to both Gs- and G(i/o)-proteins

J Neurosci. 2011 Nov 2;31(44):15629-39. doi: 10.1523/JNEUROSCI.2526-11.2011.

Authors

Sofia Cristóvão-Ferreira¹, Gemma Navarro, Marc Brugarolas, Kamil Pérez-Capote, Sandra H Vaz, Giorgia Fattorini, Fiorenzo Conti, Carmen Lluis, Joaquim A Ribeiro, Peter J McCormick, Vicent Casadó, Rafael Franco, Ana M Sebastião

Affiliation

¹ Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal.

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.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Analysis of Variance
Animals
Animals, Newborn
Astrocytes / drug effects
Astrocytes / metabolism
Bacterial Proteins / genetics
Biotinylation
Cells, Cultured
Cerebral Cortex / cytology
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Inhibitors / pharmacology
GABA Agents / pharmacology
GABA Plasma Membrane Transport Proteins / genetics
GABA Plasma Membrane Transport Proteins / metabolism*
GTP-Binding Protein alpha Subunits, Gi-Go / genetics
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
GTP-Binding Protein alpha Subunits, Gs / genetics
GTP-Binding Protein alpha Subunits, Gs / metabolism*
Gene Expression Regulation / drug effects
Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
Humans
Luminescent Proteins / genetics
Models, Biological
Nipecotic Acids / pharmacology
Phenylisopropyladenosine / metabolism
Protein Binding / drug effects
Purinergic Agents / pharmacology
Rats
Rats, Wistar
Receptors, Adenosine A2 / genetics
Receptors, Adenosine A2 / metabolism*
Recombinant Proteins / metabolism
Time Factors
Transfection / methods
Tritium / metabolism
gamma-Aminobutyric Acid / metabolism*

Substances

Bacterial Proteins
Enzyme Inhibitors
GABA Agents
GABA Plasma Membrane Transport Proteins
Luminescent Proteins
Nipecotic Acids
Purinergic Agents
Receptors, Adenosine A2
Recombinant Proteins
yellow fluorescent protein, Bacteria
Tritium
Phenylisopropyladenosine
Guanosine 5'-O-(3-Thiotriphosphate)
gamma-Aminobutyric Acid
N-(4,4-diphenyl-3-butenyl)nipecotic acid
GTP-Binding Protein alpha Subunits, Gi-Go
GTP-Binding Protein alpha Subunits, Gs