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

doi:10.1007/s11302-013-9364-5

Purinergic Signalling

September 2013, Volume 9, Issue 3, pp 433–449

A₁R–A_2AR heteromers coupled to G_s and G_i/0 proteins modulate GABA transport into astrocytes

Authors
Authors and affiliations

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. SebastiãoEmail author

Original Article

First Online:: 10 May 2013

Received:: 27 February 2013
Accepted:: 22 April 2013

DOI: 10.1007/s11302-013-9364-5

Cite this article as:: Cristóvão-Ferreira, S., Navarro, G., Brugarolas, M. et al. Purinergic Signalling (2013) 9: 433. doi:10.1007/s11302-013-9364-5

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 A_2A (A_2AR) receptors. This regulation occurs through A₁R–A_2AR heteromers that signal via two different G proteins, G_s and G_i/0, and either enhances (A_2AR) 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

References

1.
Hamilton N, Attwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11:227–238PubMedCrossRefGoogle Scholar
2.
Krnjevic K, Schwartz S (1967) The action of γ-aminobutyric acid on cortical neurons. Exp Brain Res 3:320–326PubMedCrossRefGoogle Scholar
3.
Artola A, Singer W (1987) Long-term potentiation and NMDA receptors in rat visual cortex. Nature 330:649–652PubMedCrossRefGoogle Scholar
4.
Blatow M, Rozov A, Katona I, Hormuzdi SG, Meyer AH, Whittington MA, Caputi A, Monyer H (2003) A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38:805–817PubMedCrossRefGoogle Scholar
5.
Minelli A, Brecha NC, Karschin C, DeBiasi S, Conti F (1995) GAT-1, a high-affinity GABA plasma membrane transporter, is localized to neurons and astroglia in the cerebral cortex. J Neurosci 15:7734–7746PubMedGoogle Scholar
6.
Minelli A, DeBiasi S, Brecha NC, Conti F (1996) GAT-3, a high affinity GABA plasma membrane transporter, is localized exclusively to astrocytic processes in the cerebral cortex. J Neurosci 16:6255–6264PubMedGoogle Scholar
7.
Hertz L, Schousboe A (1987) Primary cultures of GABAergic and glutamatergic neurons as model systems to study neurotransmitter functions: I. Differentiated cells. In: Model systems of development and aging of the nervous system. Giacobini E (eds). M Nijhoff Publ Com, Boston, pp 19–31
8.
Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedGoogle Scholar
9.
Correia-de-Sá P, Ribeiro JA (1994) Tonic adenosine A2A receptor activation modulates nicotinic autoreceptor function at the neuromuscular junction. Eur J Pharmacol 271:349–355PubMedCrossRefGoogle Scholar
10.
Cunha RA, Johansson B, van der Ploeg I, Sebastião AM, Ribeiro JA, Fredholm BB (1994) Evidence for functionally important adenosine A2a receptors in the rat hippocampus. Brain Res 649:208–216PubMedCrossRefGoogle Scholar
11.
Lopes LV, Cunha RA, Ribeiro JA (1999) Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol 82:3196–3203PubMedGoogle Scholar
12.
Sebastião AM, Ribeiro JA (2000) Fine-tuning neuromodulation by adenosine. Trends Pharmacol Sci 21:341–346PubMedCrossRefGoogle Scholar
13.
Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortés A, Canela EI, López-Giménez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A₁–A_2A receptor heteromers. J Neurosci 26:2080–2087PubMedCrossRefGoogle Scholar
14.
Ferré S, Navarro G, Casadó V, Cortés A, Mallol J, Canela EI, Lluís C, Franco R (2010) G protein-coupled receptor heteromers as new targets for drug development. Prog Mol Biol Transl Sci 91:41–52PubMedCrossRefGoogle Scholar
15.
Orru M, Bakešová J, Brugarolas M, Quiroz C, Beaumont V, Goldberg SR, Lluís C, Cortés A, Franco R, Casadó V, Canela EI, Ferré S (2011) Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists. PLoS One 6:e16088PubMedCrossRefGoogle Scholar
16.
Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferré S, Lluís C, Bouvier M, Franco R (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278:46741–46749PubMedCrossRefGoogle Scholar
17.
Ciruela F, Burgueño J, Casadó V, Canals M, Marcellino D, Goldberg SR, Bader M, Fuxe K, Agnati LF, Lluis C, Franco R, Ferré S, Woods AS (2004) Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A2A and dopamine D2 receptors. Anal Chem 76:5354–5363PubMedCrossRefGoogle Scholar
18.
Sarrió S, Casadó V, Escriche M, Ciruela F, Mallol J, Canela EI, Lluis C, Franco R (2000) The heat shock cognate protein hsc73 assembles with A(1) adenosine receptors to form functional modules in the cell membrane. Mol Cell Biol 20:5164–5174PubMedCrossRefGoogle Scholar
19.
Schröder R, Janssen N, Schmidt J, Kebig A, Merten N, Hennen S, Müller A, Blättermann S, Mohr-Andrä M, Zahn S, Wenzel J, Smith NJ, Gomeza J, Drewke C, Milligan G, Mohr K, Kostenis E (2010) Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat Biotechnol 28:943–949PubMedCrossRefGoogle Scholar
20.
Vaz SH, Jorgensen TN, Cristovão-Ferreira S, Duflot S, Ribeiro JA, Gether U, Sebastião AM (2011) Brain-derived neurotrophic factor (BDNF) enhances GABA transport by modulating the trafficking of GABA transporter-1 (GAT-1) from the plasma membrane of rat cortical astrocytes. J Biol Chem 286:40464–40476PubMedCrossRefGoogle Scholar
21.
Ferrada C, Moreno E, Casadó V, Bongers G, Cortés A, Mallol J, Canela EI, Leurs R, Ferré S, Lluís C, Franco R (2009) Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptor. Br J Pharmacol 157:64–75PubMedCrossRefGoogle Scholar
22.
Moreno E, Hoffmann H, Gonzalez-Sepúlveda M, Navarro G, Casadó V, Cortés A, Mallol J, Vignes M, McCormick PJ, Canela EI, Lluís C, Moratalla R, Ferré S, Ortiz J, Franco R (2011) Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem 286:5846–5854PubMedCrossRefGoogle Scholar
23.
Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KD, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131–134PubMedCrossRefGoogle Scholar
24.
Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci USA 104:654–659PubMedCrossRefGoogle Scholar
25.
Gill DM, Meren R (1978) ADP-ribosylation of membrane proteins catalyzed by cholera toxin: Basis of the activation of adenylate cyclase. Proc Natl Acad Sci USA 75:3050–3054PubMedCrossRefGoogle Scholar
26.
Bokoch GM, Gilman AG (1984) Inhibition of receptor-mediated release of arachidonic acid by pertussis toxin. Cell 39:301–308PubMedCrossRefGoogle Scholar
27.
Smith RJ, Sam LM, Justen JM, Bundy GL, Bala GA, Bleasdale JE (1990) Receptor-coupled signal transduction in human polymorphonuclear neutrophils: effects of a novel inhibitor of phospholipase C-dependent processes on cell responsiveness. J Pharmacol Exp Ther 253:688–697PubMedGoogle Scholar
28.
Wang LY, Salter MW, MacDonald JF (1991) Regulation of kainate receptors by cAMP-dependent protein kinase and phosphatases. Science 253:1132–1135PubMedCrossRefGoogle Scholar
29.
Awad JA, Johnson RA, Jakobs KH, Schultz G (1983) Interactions of forskolin and adenylate cyclase. Effects on substrate kinetics and protection against inactivation by heat and N-ethylmaleimide. J Biol Chem 258:2960–2965PubMedGoogle Scholar
30.
Xiong L, Shuhendler AJ, Rao J (2012) Self-luminescing BRET-FRET near-infrared dots for in vivo lymph-node mapping and tumour imaging. Nat Commun 3:1193PubMedCrossRefGoogle Scholar
31.
Jordan BA, Trapaidze N, Gomes I, Nivarthi R, Devi LA (2001) Oligomerization of opioid receptors with beta 2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc Natl Acad Sci U S A 98:343–348PubMedGoogle Scholar
32.
Pfeiffer M, Kirscht S, Stumm R, Koch T, Wu D, Laugsch M, Schröder H, Höllt V, Schulz S (2003) Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization. J Biol Chem 278:51630–51637PubMedCrossRefGoogle Scholar
33.
Smith NJ, Milligan G (2010) Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 62:701–725PubMedCrossRefGoogle Scholar
34.
Han Y, Moreira IS, Urizar E, Weinstein H, Javitch JA (2009) Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation. Nat Chem Biol 5:688–695PubMedCrossRefGoogle Scholar
35.
Ribeiro JA, Sebastião AM (1987) On the role, inactivation and origin of endogenous adenosine at the frog neuromuscular junction. J Physiol 384:571–585PubMedGoogle Scholar
36.
Cunha RA, Vizi ES, Ribeiro JA, Sebastião AM (1996) Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high- but not low-frequency stimulation of rat hippocampal slices. J Neurochem 67:2180–2187PubMedCrossRefGoogle Scholar
37.
Lovatt D, Xu Q, Liu W, Takano T, Smith NA, Schnermann J, Tieu K, Nedergaard M (2012) Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity. Proc Natl Acad Sci U S A 109:6265–6270PubMedCrossRefGoogle Scholar
38.
Lee HU, Yamazaki Y, Tanaka KF, Furuya K, Sokabe M, Hida H, Takao K, Miyakawa T, Fujii S, Ikenaka K (2013) Increased astrocytic ATP release results in enhanced excitability of the hippocampus. Glia 61:210–224PubMedCrossRefGoogle Scholar
39.
Fields RD, Burnstock G (2006) Purinergic signalling in neuron–glia interactions. Nat Rev Neurosci 7:423–436PubMedCrossRefGoogle Scholar
40.
Klotz KN, Hessling J, Hegler J, Owman C, Kull B, Fredholm BB, Lohse MJ (1998) Comparative pharmacology of human adenosine receptor subtypes—characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 357:1–9PubMedCrossRefGoogle Scholar
41.
Linden J, Thai T, Figler H, Jin X, Robeva AS (1999) Characterization of human A(2B) adenosine receptors: radioligand binding, western blotting, and coupling to G(q) in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol 56:705–713PubMedGoogle Scholar
42.
Ongini E, Dionisotti S, Gessi S, Irenius E, Fredholm BB (1999) Comparison of CGS 15943, ZM 241385 and SCH 58261 as antagonists at human adenosine receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 359:7–10CrossRefGoogle Scholar
43.
Ji XD, Jacobson KA (1999) Use of the triazolotriazine [3H]ZM 241385 as a radioligand at recombinant human A2B adenosine receptors. Drug Des Discov 16:217–226PubMedGoogle Scholar

Copyright information

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
Email author

1.Institute of Pharmacology and Neurosciences, Faculty of MedicineUniversity of LisbonLisbonPortugal
2.Unit of Neurosciences, Institute of Molecular MedicineUniversity of LisbonLisbonPortugal
3.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)University of BarcelonaBarcelonaSpain
4.Department of Biochemistry and Molecular Biology, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain
5.Department of NeuroscienceUniversità Politecnica delle MarcheAnconaItaly
6.Center for Neurobiology of AgingINRCA IRCCSAnconaItaly
7.Fondazione di Medicina MolecolareUniversità Politecnica delle MarcheAnconaItaly
8.Laboratory of Cell and Molecular Neuropharmacology, Neurosciences Division, Centro de Investigación Médica Aplicada (CIMA)University of NavarraPamplonaSpain

Personalised recommendations

Article actions

Unlimited access to the full article
Instant download
Include local sales tax if applicable

Subscribe to Journal

Get Access to