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Purinergic Signalling

, Volume 9, Issue 3, pp 433–449 | Cite as

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

  • 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
Original Article

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.

Keywords

Adenosine heteromers G protein coupling GABA transporters Astrocytes 

Notes

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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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Sofia Cristóvão-Ferreira
    • 1
    • 2
  • Gemma Navarro
    • 3
    • 4
  • Marc Brugarolas
    • 3
    • 4
  • Kamil Pérez-Capote
    • 3
    • 4
  • Sandra H. Vaz
    • 1
    • 2
  • Giorgia Fattorini
    • 5
    • 6
  • Fiorenzo Conti
    • 5
    • 6
    • 7
  • Carmen Lluis
    • 3
    • 4
  • Joaquim A. Ribeiro
    • 1
    • 2
  • Peter J. McCormick
    • 3
    • 4
  • Vicent Casadó
    • 3
    • 4
  • Rafael Franco
    • 3
    • 4
    • 8
  • Ana M. Sebastião
    • 1
    • 2
  1. 1.Institute of Pharmacology and Neurosciences, Faculty of MedicineUniversity of LisbonLisbonPortugal
  2. 2.Unit of Neurosciences, Institute of Molecular MedicineUniversity of LisbonLisbonPortugal
  3. 3.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)University of BarcelonaBarcelonaSpain
  4. 4.Department of Biochemistry and Molecular Biology, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain
  5. 5.Department of NeuroscienceUniversità Politecnica delle MarcheAnconaItaly
  6. 6.Center for Neurobiology of AgingINRCA IRCCSAnconaItaly
  7. 7.Fondazione di Medicina MolecolareUniversità Politecnica delle MarcheAnconaItaly
  8. 8.Laboratory of Cell and Molecular Neuropharmacology, Neurosciences Division, Centro de Investigación Médica Aplicada (CIMA)University of NavarraPamplonaSpain

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