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Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function

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Abstract

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A-D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the 13 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of 13 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson’s disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.

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References

  • Agnati L. F., Ferré S., Lluis C., Franco R., and Fuxe K. (2003) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacol. Rev. 55, 509–550.

    Article  PubMed  CAS  Google Scholar 

  • Agnati L. F., Fuxe K., Zini I., Lenzi P., and Hökfelt T. (1980) Aspects on receptor regulation and isoreceptor identification. Med. Biol. 58, 182–187.

    PubMed  CAS  Google Scholar 

  • Andersen M. B., Fuxe K., Werge T., and Gerlach J. (2002) The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys. Behav. Pharmacol. 13, 639–644.

    PubMed  CAS  Google Scholar 

  • Bara-Jimenez W., Sherzai A., Dimitrova T., Favit A., Bibbiani F., Gillespie M., et al. (2003) Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology 61, 293–296.

    PubMed  CAS  Google Scholar 

  • Bofill-Cardona E., Kudlacek O., Yang Q., Ahorn H., Freissmuth M., and Nanoff C. (2000) Binding of calmodulin to the D2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch. J. Biol. Chem. 275, 32672–32680.

    Article  PubMed  CAS  Google Scholar 

  • Canals M., Burgueno J., Marcellino D., Cabello N., Canela E. I., Mallol J., et al. (2004) Homodimerization of adenosine A2A receptors. Qualitative and quantitative assessment by fluorescence and bioluminescence transfer. J. Neurochem. 88, 726–734.

    Article  PubMed  CAS  Google Scholar 

  • Canals M., Marcellino D., Fanelli F., Ciruela F., de Benedetti P., Goldberg S., et al. (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization. Qualitative and quantitative assessment of fluorescence and bioluminescence energy transfer. J. Biol. Chem. 278, 46741–46749.

    Article  PubMed  CAS  Google Scholar 

  • Ciruela F., Burgueno J., Casado V., Canals M., Marcelino D., Goldberg S. R., et al. (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, 5354–5363.

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta S., Ferré S., Kull B., Hedlund P. B., Finnman U.-B., Ahlberg S., et al. (1996) Adenosine A2A receptors modulate the binding characteristics of dopamine D2 receptors in stably cotransfected fibroblast cells. Eur. J. Pharmacol. 316, 325–331.

    Article  PubMed  CAS  Google Scholar 

  • Díaz-Cabiale Z., Hurd Y., Guidolin D., Finnman U. B., Zoli M., Agnati L. F., et al. (2001) Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum. NeuroReport 12, 1831–1834.

    Article  PubMed  Google Scholar 

  • Ferré S. (1997) Adenosine-dopamine interactions in the ventral striatum. Implications for the treatment of schizophrenia. Psychopharmacology 133, 107–120.

    Article  PubMed  Google Scholar 

  • Ferré S. and Fuxe K. (1992) Dopamine denervation leads to an increase in the membrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum. Brain Res. 594, 124–130.

    Article  PubMed  Google Scholar 

  • Ferré S., Ciruela F., Canals M., Marcellino D., Burgueno J., Casado V., et al. (2004) Adenosine A2A-dopamine D2 receptor-receptor heteromers. Targets for neuro-psychiatric disorders. Parkinsonism Relat. Disord. 10, 265–271.

    Article  PubMed  Google Scholar 

  • Ferré S., Ciruela F., Woods A. S., Canals M., Burgueno J., Marcellino D., et al. (2003) Glutamate mGlu5-adenosine A2A-dopamine D2 receptor interactions in the striatum. Implications for drug therapy in neuropsychiatric disorders and drug abuse. Curr. Med. Chem. CNS Agents 33, 1–26.

    Google Scholar 

  • Ferré S., Fredholm B. B., Morelli M., Popoli P., and Fuxe K. (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 20, 482–487.

    Article  PubMed  Google Scholar 

  • Ferré S., Fuxe K., von Euler G., Johansson B., and Fredholm B. B. (1992) Adenosine-dopamine interactions in the brain. Neuroscience 51, 501–512.

    Article  PubMed  Google Scholar 

  • Ferré S., Karcz-Kubicha M., Hope B. T., Popoli P., Burgueno J., Casado V., et al. (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: Implications for striatal neuronal function. Proc. Natl. Acad. Sci. U. S. A. 99, 11940–11945.

    Article  PubMed  CAS  Google Scholar 

  • Ferré S., O’Connor W. T., Snaprud P., Ungerstedt U., and Fuxe K. (1994) Antagonistic interaction between adenosine A2A and dopamine D2 receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. Neuroscience 63, 765–773.

    Article  PubMed  Google Scholar 

  • Ferré S., Popoli P., Giménez-Llort L., Rimondini R., Müller C. E., Strömberg I., et al. (2001) Adenosine/dopamine interaction: implications for the treatment of Parkinson’s disease. Parkinsonism Relat. Disord. 7, 235–241.

    Article  PubMed  Google Scholar 

  • Ferré S., von Euler G., Johansson B., Fredholm B. B., and Fuxe K. (1991) Stimulation of high affinity adenosine A-2 receptors decreases the affinity of dopamine D-2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U. S. A. 88, 7238–7241.

    Article  PubMed  Google Scholar 

  • Fink J. S., Weaver D. R., Rivkees S. A., Peterfreund R. A., Pollack A., Adler E. M., and Reppert S. M. (1992) Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Mol. Brain Res. 14, 186–195.

    Article  PubMed  CAS  Google Scholar 

  • Fuxe K., Agnati L. F., Benfenati F., Cimmino M., Algeri S., and Hökfelt T. (1981) Modulation by cholecystokinins of [3H]spiroperidol binding in rat striatum: evidence for increased affinity and reduction in the number of binding sites. Acta Physiol. Scand. 113, 567–569.

    Article  PubMed  CAS  Google Scholar 

  • Fuxe K., Agnati L. F., Jacobsen K., Hillion J., Canals M., Torvinen M., et al. (2003) On the role of receptor heteromerization in adenosine A2A receptor signaling. Relevance for striatal function and Parkinson’s disease. Neurology 61(Suppl. 6), S19-S23.

    PubMed  CAS  Google Scholar 

  • Fuxe K. and Agnati L. F. (1985) Receptor-receptor interactions in the central nervous system. A new integrative mechanism in synapses. Med. Res. Rev. 5, 441–482.

    Article  PubMed  CAS  Google Scholar 

  • Fuxe K. and Agnati L. F. (1987) Receptor-Receptor Interactions. A New Intramembrane Integrative Mechanism. Macmillan Press, London, UK.

    Google Scholar 

  • Fuxe K. and Ungerstedt U. (1974) Action of caffeine and theophyllamine on supersensitive dopamine receptors: considerable enhancement of receptor response to treatment with dopa and dopamine receptor agonists. Med. Biol. 52, 48–54.

    PubMed  CAS  Google Scholar 

  • Fuxe K., Ferré S., Zoli M., and Agnati L. F. (1998) Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intra membrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res. Rev. 26, 258–273.

    Article  PubMed  CAS  Google Scholar 

  • Fuxe K., Strömberg I., Popoli P., Rimondini-Giorgini R., Torvinen M., Ogren S. O., et al. (2001) Adenosine receptors and Parkinson’s disease. Relevance of antagonistic adenosine and dopamine receptor interactions in the striatum. Adv. Neurol. 86, 345–353.

    PubMed  CAS  Google Scholar 

  • Gouldson P. R., Higgs C., Smith R. E., Dean M. K., Gkoutos G. V., and Reynolds C. A. (2000) Dimerization and domain swapping in G-protein-coupled receptors: a computational study. Neuropsychopharmacology 23, 60–77.

    Article  Google Scholar 

  • Guo W., Shi L., and Javitch J. A. (2003) The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer. J. Biol. Chem. 278, 4385–4388.

    Article  PubMed  CAS  Google Scholar 

  • Hauser R. A., Hubble J. P., and Truong D. D. (2003) Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology 61, 297–303.

    PubMed  CAS  Google Scholar 

  • Hettinger B. D., Lee A., Linden J., and Rosin D. L. (2001) Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. J. Comp. Neurol. 431, 331–346.

    Article  PubMed  CAS  Google Scholar 

  • Hillefors M., Hedlund P. B., and von Euler G. (1999) Effects of adenosine A(2A) receptor stimulation in vivo on dopamine D3 receptor agonist binding in the rat brain. Biochem. Pharmacol. 58, 1961–1964.

    Article  PubMed  CAS  Google Scholar 

  • Hillion J., Canals M., Torvinen M., Casado V., Scott R., Terasmaa A., et al. (2002) Coaggregation, cointernalization and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem. 277, 18091–18097.

    Article  PubMed  CAS  Google Scholar 

  • Kamiya T., Saitoh O., Yoshioka K., and Nakata H. (2003) Oligomerization of adenosine A2A and dopamine D2 receptors in living cells. Biochem. Biophys. Res. Commun. 306, 544–549.

    Article  PubMed  CAS  Google Scholar 

  • Kudlacek O., Just H., Korkhov V. M., Vartian N., Klinger M., Pankevych H., et al. (2003) The human D2 dopamine receptor synergizes with the A2A adenosine receptor to stimulate adenylyl cyclase in PC12 cells. Neuropsychopharmacology 28, 1317–1327.

    Article  PubMed  CAS  Google Scholar 

  • Kull B., Ferré S., Arslan G., Svenningsson P., Fuxe K., Owman C., and Fredholm B. B. (1999) Reciprocal interactions between adenosine A2A and dopamine D2 receptors in Chinese hamster ovary cells co-transfected with the two receptors. Biochem. Pharmacol. 58, 1035–1045.

    Article  PubMed  CAS  Google Scholar 

  • Lee K. W., Hong J. H., Choi I. Y., Che Y., Lee J. K., Yang S. D., et al. (2002) Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase. J. Neurosci. 22, 7931–7940.

    PubMed  CAS  Google Scholar 

  • Lee S. P., Xie Z., Varghese G., Nguyen T., O’Dowd B. F., and George S. (2000) Oligomerization of dopamine and serotonin receptors. Neuropsychopharmacology 23, S32-S40.

    Article  PubMed  CAS  Google Scholar 

  • Mellado M., Vila-Coro A. J., Martinez C., and Rodriguez-Frade J. M. (2002) Receptor dimerization: a key step in chemokine signaling. Cell. Mol. Biol. 47, 575–582.

    Google Scholar 

  • Nimchinsky E. A., Hof P. R., Janssen W. G., Morrison J. H., and Schmauss C. (1997) Expression of dopamine D3 receptor dimers and tetramers in brain an in transfected cells. J. Biol. Chem. 272, 29229–29237.

    Article  PubMed  CAS  Google Scholar 

  • Patel R. C., Kumar U., Lamb D. C., Eid J. S., Rocheville M., Grant M., et al. (2002) Ligand binding to somatostatin receptors induces receptor-specific oligomer formation in live cells. Proc. Natl. Acad. Sci. U. S. A. 99, 3294–3299.

    Article  PubMed  CAS  Google Scholar 

  • Rimondini R., Ferré S., Ogren S. O., and Fuxe K. (1997) Adenosine A2A agonists: a potential new type of atypical antipsychotic. Neuropsychopharmacology 17, 82–91.

    Article  PubMed  CAS  Google Scholar 

  • Rocheville M., Lange D. C., Kumar U., Patel S. C., Patel R. C., and Patel Y. C. (2000) Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157.

    Article  PubMed  CAS  Google Scholar 

  • Salim H., Ferré S., Dalal A., Peterfreund R. A., Fuxe K., Vincent J. - D., and Lledo P. M. (2000) Activation of adenosine A1 and A2A receptors modulates dopamine D2 receptor-induced responses in stably transfected human neuroblastoma cells. J. Neurochem. 74, 432–439.

    Article  PubMed  CAS  Google Scholar 

  • Scarselli M., Novi F., Schallmach E., Lin R., Baragli A., Colzi A., et al. (2001) D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J. Biol. Chem. 276, 30308–30314.

    Article  PubMed  CAS  Google Scholar 

  • Schiffmann S. N., Jacobs O., and Vanderhaeghen J.-J. (1991) Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study. J. Neurochem. 57, 1062–1067.

    Article  PubMed  CAS  Google Scholar 

  • Schwartz J. C., Diaz J., Pilon C., and Sokoloff P. (2000) Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res. Brain. Res. Rev. 31, 277–287.

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson P., Lindskog M., Ledent C., Parmentier M., Greengard P., Fredholm B. B., and Fisone G. (2000) Regulation of the phosphorylation of the dopamineand cAMP-regulated phosphoprotein of 32 kDa in vivo by dopamine D1, dopamine D2, and adenosine A2A receptors. Proc. Natl. Acad. Sci. U. S. A. 97, 1856–1860.

    Article  PubMed  CAS  Google Scholar 

  • Tanganelli S., Sandager Nielsen K., Ferraro L., Antonelli T., Kehr J., Franco R., et al. (2004) Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson’s disease. Parkinsonism Relat. Disord. 10, 273–280.

    Article  PubMed  CAS  Google Scholar 

  • Terrillon S. and Bouvier M. (2004) Roles of G-protein-coupled receptor dimerization. EMBO Rep. 5, 30–34.

    Article  PubMed  CAS  Google Scholar 

  • Torvinen M., Kozell L. B., Neve K. A., Agnati L. F., and Fuxe K. (2004a) Biochemical identification of dopamine D2 receptor domains interacting with the adenosine A2A receptor. J. Mol. Neurosci. 24, 273–280.

    Article  Google Scholar 

  • Torvinen M., Torri C., Tombesi A., Marcellino D., Watson S., Lluis C., et al. (2005a) Trafficking of adenosine A2A and dopamine D2 receptors. J. Mol. Neurosci., 25, 191–200.

    Article  PubMed  CAS  Google Scholar 

  • Torvinen M., Marcellino D., Canals M., Agnati L., F., Lluis C., Franco R., and Fuxe K. (2004c) Adenosine A2A receptor and dopamine D3 receptor interactions: Evidence of functional A2A/D3 heteromeric complexes. Mol. Pharmacol. 67, 400–407.

    Article  PubMed  CAS  Google Scholar 

  • Vortherms T. A. and Watts V. J. (2004) Sensitization of neuronal A2A adenosine receptors. after persistent D2 dopamine receptor activation. J. Pharmacol. Exp. Ther. 308, 221–227.

    Article  PubMed  CAS  Google Scholar 

  • Yao L., Arolfo M. P., Dohrman D. P., Jiang Z., Fan P., Fuchs S., et al. (2002) βγ Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. Cell 109, 733–743.

    Article  PubMed  CAS  Google Scholar 

  • Zoli M., Agnati L. F., Hedlung P. B., Li X. M., Ferré S., and Fuxe K. (1993) Receptor-receptor interactions as an integrative mechanism in nerve cells. Mol. Neurobiol. 7, 293–334.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, Stockholm, Sweden

    Kjell Fuxe, Meritxell Canals, Maria Torvinen & Anton Terasmaa

  2. Department of Biochemistry and Molecular Biology, University of Barcelona, Spain

    Daniel Marcellino, Carmen Lluis & Rafael Franco

  3. Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada

    William Staines & Kirsten X. Jacobsen

  4. National Institute on Drug Abuse, DHHS, NIH, Intramural Research Program, 21224, Baltimore, MD

    Sergi Ferré, Steven R. Goldberg & Amina s. Woods

  5. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Luigi F. Agnati

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  1. Kjell Fuxe
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  2. Sergi Ferré
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Fuxe, K., Ferré, S., Canals, M. et al. Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J Mol Neurosci 26, 209–220 (2005). https://doi.org/10.1385/JMN:26:2-3:209

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