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A1R–A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes

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A Correction to this article was published on 27 April 2024

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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.

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Acknowledgments

We acknowledge the technical help obtained from Jasmina Jiménez (Molecular Neurobiology laboratory, Barcelona University). This study was supported by Fundação para a Ciência e a Tecnologia (FCT) project grants, COST B30 action, grants from Spanish Ministerio de Ciencia y Tecnología (SAF2008-03229-E, SAF2008-00146), and funds from PRIN and Università Politecnica delle Marche (to F.C.). PJM is a Ramón y Cajal Fellow. SC-F is in receipt of an FCT fellowship (SFRH/BD/38099/2007).

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Authors and Affiliations

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

    Sofia Cristóvão-Ferreira, Sandra H. Vaz, Joaquim A. Ribeiro & Ana M. Sebastião

  2. Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Av. Professor Egas Moniz, Edificio Egas Moniz, 1649-028, Lisbon, Portugal

    Sofia Cristóvão-Ferreira, Sandra H. Vaz, Joaquim A. Ribeiro & Ana M. Sebastião

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Barcelona, Barcelona, Spain

    Gemma Navarro, Marc Brugarolas, Kamil Pérez-Capote, Carmen Lluis, Peter J. McCormick, Vicent Casadó & Rafael Franco

  4. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain

    Gemma Navarro, Marc Brugarolas, Kamil Pérez-Capote, Carmen Lluis, Peter J. McCormick, Vicent Casadó & Rafael Franco

  5. Department of Neuroscience, Università Politecnica delle Marche, Ancona, Italy

    Giorgia Fattorini & Fiorenzo Conti

  6. Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy

    Giorgia Fattorini & Fiorenzo Conti

  7. Fondazione di Medicina Molecolare, Università Politecnica delle Marche, Ancona, Italy

    Fiorenzo Conti

  8. Laboratory of Cell and Molecular Neuropharmacology, Neurosciences Division, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain

    Rafael Franco

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  1. Sofia Cristóvão-Ferreira
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  2. Gemma Navarro
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Correspondence to Ana M. Sebastião.

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Cristóvão-Ferreira, S., Navarro, G., Brugarolas, M. et al. A1R–A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes. Purinergic Signalling 9, 433–449 (2013). https://doi.org/10.1007/s11302-013-9364-5

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