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Adenosine Receptors as a Paradigm to Identify Dimer/Oligomers of G-Protein-Coupled Receptors and as Targets in Parkinson’s Disease and Schizophrenia

  • Gemma Navarro
  • Dasiel O. Borroto-Escuela
  • Kiell Fuxe
  • Rafael Franco
Chapter
Part of the The Receptors book series (REC, volume 34)

Abstract

While adrenergic receptors were instrumental to start to understand the role of GPCRs, other receptors are taking the lead to understand why GPCR homo−/heteromers are needed and to address their physiological consequences in both healthy/homeostatic conditions and disease. Adenosine and dopamine receptors in the CNS are instrumental to understand pathogenic mechanisms in Parkinson’s disease and to know the role of receptor heteromers. We here provide the account of the heteroreceptor complexes formed by adenosine receptors (A1, A2A, A2B, and A3), and their potential as therapeutic targets. Both adenosine (A1 or A2A)-dopamine (D1 or D2) and adenosine A1A2A heteroreceptor complexes are therapeutic targets in Parkinson’s disease and may be altered after chronic levodopa treatment. A short account on the potential of adenosine receptors as targets in schizophrenia is also provided. Apart from potential in combating symptoms, adenosine receptors have potential as targets for neuroprotection. However, the design of neuroprotective drugs requires to understand how adenosine affects microglia and which adenosine-receptor-containing heteromers may be targeted.

Keywords

Adenosine receptors Heteroreceptor complexes Dopamine receptors Parkinson’s disease Schizophrenia 

References

  1. Agnati LF, Fuxe K, Zoli M et al (1982) New vistas on synaptic plasticity: the receptor mosaic hypothesis of the engram. Med Biol 60:183–190PubMedPubMedCentralGoogle Scholar
  2. Agnati LF, Leo G, Vergoni AV et al (2004) Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson’s disease. Brain Res Bull 64:155–164PubMedCrossRefPubMedCentralGoogle Scholar
  3. Armentero MT, Pinna A, Ferré S et al (2011) Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132:280–299PubMedPubMedCentralCrossRefGoogle Scholar
  4. Beamer E, Gölöncsér F, Horváth G et al (2016) Purinergic mechanisms in neuroinflammation: an update from molecules to behavior. Neuropharmacology 104:94–104PubMedCrossRefPubMedCentralGoogle Scholar
  5. Beggiato S, Antonelli T, Tomasini MC et al (2014) Adenosine A2A-D2 receptor-receptor interactions in putative heteromers in the regulation of the striato-pallidal gaba pathway: possible relevance for parkinson’s disease and its treatment. Curr Protein Pept Sci 15:673–680PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bibbiani F, Oh JD, Petzer JP et al (2003) A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Exp Neurol 184:285–294PubMedCrossRefPubMedCentralGoogle Scholar
  7. Birkmayer W, Hornykiewicz O (1962) The L-dihydroxyphenylalanine (L-DOPA) effect in Parkinson’s syndrome in man: on the pathogenesis and treatment of Parkinson akinesis. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 203:560–574PubMedCrossRefPubMedCentralGoogle Scholar
  8. Birkmayer W, Hornykiewicz O (1964) Additional experimental studies on L-DOPA in Parkinson’s syndrome and reserpine parkinsonism. Arch Psychiatr Nervenkr 206:367–381PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bogenpohl JW, Ritter SL, Hall RA et al (2012) Adenosine A2A receptor in the monkey basal ganglia: ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum. J Comp Neurol 520:570–589PubMedPubMedCentralCrossRefGoogle Scholar
  10. Boia R, Elvas F, Madeira MH et al (2017) Treatment with A2A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage. Cell Death Dis 8:e3065PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bonaventura J, Rico AJ, Moreno E et al (2014) L-DOPA-treatment in primates disrupts the expression of A2A adenosine-CB1 cannabinoid-D2 dopamine receptor heteromers in the caudate nucleus. Neuropharmacology 79:90–100PubMedCrossRefPubMedCentralGoogle Scholar
  12. Borroto-Escuela DO, Fuxe K (2017) Diversity and bias through dopamine D2R heteroreceptor complexes. Curr Opin Pharmacol 32:16–22PubMedCrossRefPubMedCentralGoogle Scholar
  13. Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO et al (2010) Characterization of the A2AR-D2R interface: focus on the role of the C-terminal tail and the transmembrane helices. Biochem Biophys Res Commun 402:801–807PubMedCrossRefPubMedCentralGoogle Scholar
  14. Borroto-Escuela DO, Romero-Fernandez W, Tarakanov AO et al (2011) On the existence of a possible A2A-D2-β-Arrestin2 complex: A2A agonist modulation of D2 agonist-induced β-arrestin2 recruitment. J Mol Biol 406:687–699PubMedCrossRefPubMedCentralGoogle Scholar
  15. Borroto-Escuela DO, Brito I, Romero-Fernandez W et al (2014) The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components. Int J Mol Sci 15:8570–8590PubMedPubMedCentralCrossRefGoogle Scholar
  16. Borroto-Escuela DO, Wydra K, Pintsuk J et al (2016) Understanding the functional plasticity in neural networks of the basal ganglia in cocaine use disorder: a role for allosteric receptor-receptor interactions in A2A-D2 heteroreceptor complexes. Neural Plast 2016:1–12CrossRefGoogle Scholar
  17. Borroto-Escuela D, Narváez M, Navarro G et al (2017a) Heteroreceptor complexes implicated in Parkinson’s disease. In: G-protein-coupled receptor dimers. The Receptors, vol 33. Humana Press, Cham, pp 477–501CrossRefGoogle Scholar
  18. Borroto-Escuela DO, Narváez M, Wydra K et al (2017b) Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder. Pharmacol Biochem Behav 155:24–31PubMedCrossRefPubMedCentralGoogle Scholar
  19. Cabello N, Gandía J, DCG B et al (2009) Metabotropic glutamate type 5, dopamine D 2 and adenosine A 2a receptors form higher-order oligomers in living cells. J Neurochem 109:1497–1507PubMedPubMedCentralCrossRefGoogle Scholar
  20. Canals M, Marcellino D, Fanelli F et al (2003) Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem 278:46741–46749PubMedCrossRefPubMedCentralGoogle Scholar
  21. Canals M, Burgueño J, Marcellino D et al (2004) Homodimerization of adenosine A2A receptors: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Neurochem 88:726–734PubMedCrossRefPubMedCentralGoogle Scholar
  22. Cao Y, Sun WC, Jin L et al (2006) Activation of adenosine A1 receptor modulates dopamine D1 receptor activity in stably cotransfected human embryonic kidney 293 cells. Eur J Pharmacol 548:29–35PubMedCrossRefPubMedCentralGoogle Scholar
  23. Carriba P, Ortiz O, Patkar K et al (2007) Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology 32:2249–2259PubMedCrossRefPubMedCentralGoogle Scholar
  24. Chandrasekera PC, Wan TC, Gizewski ET et al (2013) Adenosine A1 receptors heterodimerize with β1- and β2-adrenergic receptors creating novel receptor complexes with altered G protein coupling and signaling. Cell Signal 25:736–742PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chen JF, Pedata F (2008) Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Curr Pharm Des 14:1490–1499PubMedCrossRefPubMedCentralGoogle Scholar
  26. Ciruela F, Casadó V, Mallol J et al (1995) Immunological identification of A1 adenosine receptors in brain cortex. J Neurosci Res 42:818–828PubMedCrossRefPubMedCentralGoogle Scholar
  27. Ciruela F, Escriche M, Burgueno J et al (2001) Metabotropic glutamate 1alpha and adenosine A1 receptors assemble into functionally interacting complexes. J Biol Chem 276:18345–18351PubMedCrossRefPubMedCentralGoogle Scholar
  28. Ciruela F, Burgueño J, Casadó V 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 D2receptors. Anal Chem 76:5354–5363PubMedCrossRefPubMedCentralGoogle Scholar
  29. Ciruela F, Casadó V, Rodrigues RJ et al (2006) Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. J Neurosci 26:2080–2087PubMedCrossRefPubMedCentralGoogle Scholar
  30. Cordomí A, Navarro G, Aymerich MS et al (2015) Structures for G-protein-coupled receptor tetramers in complex with G proteins. Trends Biochem Sci 40:548–551PubMedCrossRefPubMedCentralGoogle Scholar
  31. Corriden R, Insel PA (2012) New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors. Purinergic Signal 8:587–598PubMedPubMedCentralCrossRefGoogle Scholar
  32. Corset V, Nguyen-Ba-Charvet KT, Forcet C et al (2000) Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature 407:747–750PubMedCrossRefPubMedCentralGoogle Scholar
  33. Cristóvão-Ferreira S, Navarro G, Brugarolas M et al (2013) A1R-A2AR heteromers coupled to Gs and G i/o proteins modulate GABA transport into astrocytes. Purinergic Signal 9:433–449PubMedPubMedCentralCrossRefGoogle Scholar
  34. Doumazane E, Scholler P, Zwier JM et al (2011) A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J 25:66–77PubMedCrossRefPubMedCentralGoogle Scholar
  35. Dunham JH, Meyer RC, Garcia EL et al (2009) GPR37 surface expression enhancement via N-terminal truncation or protein-protein interactions. Biochemistry 48:10286–10297PubMedPubMedCentralCrossRefGoogle Scholar
  36. Escriche M, Burgueño J, Ciruela F et al (2003) Ligand-induced caveolae-mediated internalization of A1 adenosine receptors: morphological evidence of endosomal sorting and receptor recycling. Exp Cell Res 285:72–90PubMedCrossRefPubMedCentralGoogle Scholar
  37. Farré D, Muñoz A, Moreno E et al (2015) Stronger dopamine D1 receptor-mediated neurotransmission in dyskinesia. Mol Neurobiol 52:1408–1420PubMedCrossRefPubMedCentralGoogle Scholar
  38. Ferré S, O’Connor WT, Snaprud P et al (1994) Antagonistic interaction between adenosine A2A receptors and dopamine D2 receptors in the ventral striopallidal system implications for the treatment of schizophrenia. Neuroscience 63:765–773PubMedCrossRefPubMedCentralGoogle Scholar
  39. Ferré S, Karcz-Kubicha M, Hope BT et al (2002) Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proc Natl Acad Sci U S A 99:11940–11945PubMedPubMedCentralCrossRefGoogle Scholar
  40. Ferré S, Ciruela F, Woods AS et al (2003) Glutamate mGluR5/adenosine A2A/dopamine D2 receptor, interactions in the striatum implications for drug therapy in neuro-psychiatric disorders and drug abuse. Curr Med Chem Cent Nerv Syst Agents 3:1–26CrossRefGoogle Scholar
  41. Ferré S, Agnati LF, Ciruela F et al (2007a) Neurotransmitter receptor heteromers and their integrative role in ‘local modules’: the striatal spine module. Brain Res Rev 55:55–67PubMedPubMedCentralCrossRefGoogle Scholar
  42. Ferré S, Ciruela F, Woods AS et al (2007b) Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends Neurosci 30:440–446PubMedCrossRefPubMedCentralGoogle Scholar
  43. Ferre S, Ciruela F, Borycz J et al (2008) Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain. Front Biosci 13:2391–2399PubMedCrossRefPubMedCentralGoogle Scholar
  44. Ferré S, Baler R, Bouvier M et al (2009a) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131–134PubMedPubMedCentralCrossRefGoogle Scholar
  45. Ferré S, Goldberg SR, Lluis C et al (2009b) Looking for the role of cannabinoid receptor heteromers in striatal function. Neuropharmacology 56:226–234PubMedCrossRefPubMedCentralGoogle Scholar
  46. Ferré S, Lluís C, Justinova Z et al (2010a) Adenosine-cannabinoid receptor interactions implications for striatal function. Br J Pharmacol 160(3):443–453PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ferré S, Woods AS, Navarro G et al (2010b) Calcium-mediated modulation of the quaternary structure and function of adenosine A2A-dopamine D2 receptor heteromers. Curr Opin Pharmacol 10:67–72PubMedCrossRefPubMedCentralGoogle Scholar
  48. Florán B, Barajas C, Florán L et al (2002) Adenosine A1 receptors control dopamine D1-dependent [(3)H]GABA release in slices of substantia nigra pars reticulata and motor behavior in the rat. Neuroscience 115:743–751PubMedCrossRefPubMedCentralGoogle Scholar
  49. Franco R, Fernández-Suárez D (2015) Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol 131:65–86PubMedCrossRefPubMedCentralGoogle Scholar
  50. Franco R, Ferré S, Torvinen M et al (2001) Adenosine/dopamine receptor-receptor interactions in the central nervous system. Drug Dev Res 52:296–302CrossRefGoogle Scholar
  51. Franco R, Ciruela F, Casadó V et al (2005) Partners for adenosine A1receptors. J Mol Neurosci 26:221–231PubMedCrossRefPubMedCentralGoogle Scholar
  52. Franco R, Lluis C, Canela EI et al (2007) Receptor-receptor interactions involving adenosine A1 or dopamine D1 receptors and accessory proteins. J Neural Transm 114:93–104PubMedCrossRefPubMedCentralGoogle Scholar
  53. Franco R, Martínez-Pinilla E, Lanciego JL et al (2016) Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front Pharmacol 7:76PubMedPubMedCentralCrossRefGoogle Scholar
  54. Franco R, Navarro G (2018) Adenosine A2A Receptor Antagonists in Neurodegenerative Diseases: Huge Potential and Huge Challenges. Front Psychiatry 9:68Google Scholar
  55. Fuxe K, Agnati LF (1985) Receptor-receptor interactions in the central nervous system A new integrative mechanism in synapses. Med Res Rev 5:441–482PubMedCrossRefPubMedCentralGoogle Scholar
  56. Fuxe K, 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 52:48–54PubMedPubMedCentralGoogle Scholar
  57. Fuxe K, Agnati LF, Benfenati F et al (1981) Modulation by cholecystokinins of 3 H-spiroperidol binding in rat striatum: evidence for increased affinity and reduction in the number of binding sites. Acta Physiol Scand 113:567–569PubMedCrossRefPubMedCentralGoogle Scholar
  58. Fuxe K, Agnati LF, Benfenati F et al (1983) Evidence for the existence of receptor--receptor interactions in the central nervous system studies on the regulation of monoamine receptors by neuropeptides. J Neural Transm Suppl 18:165–179PubMedPubMedCentralGoogle Scholar
  59. Fuxe K, Härfstrand A, Agnati LF et al (1987) Central catecholamine-neuropeptide Y interactions at the pre- and postsynaptic level in cardiovascular centers. J Cardiovasc Pharmacol 10(Suppl 1):1–13Google Scholar
  60. Fuxe K, Ferré S, Zoli M et al (1998) Integrated events in central dopamine transmission as analyzed at multiple levels evidence for intramembrane adenosine A2A/dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res Brain Res Rev 26:258–273PubMedCrossRefPubMedCentralGoogle Scholar
  61. Fuxe K, Agnati LFF, Jacobsen K et al (2003) Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology 61:S19–S23PubMedCrossRefPubMedCentralGoogle Scholar
  62. Fuxe K, Ferré S, Canals M et al (2005) Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function. J Mol Neurosci 26:209–220PubMedCrossRefPubMedCentralGoogle Scholar
  63. Fuxe K, Marcellino D, Genedani S et al (2007) Adenosine A2A receptors dopamine D2 receptors and their interactions in Parkinson’s disease. Mov Disord 22:1990–2017PubMedCrossRefPubMedCentralGoogle Scholar
  64. Fuxe K, Marcellino D, Rivera A et al (2008) Receptor–receptor interactions within receptor mosaics impact on neuropsychopharmacology. Brain Res Rev 58:415–452PubMedCrossRefPubMedCentralGoogle Scholar
  65. Fuxe K, Marcellino D, Leo G et al (2010) Molecular integration via allosteric interactions in receptor heteromers A working hypothesis. Curr Opin Pharmacol 10:14–22PubMedCrossRefPubMedCentralGoogle Scholar
  66. Fuxe K, Borroto-Escuela D, Fisone G et al (2014a) Understanding the role of heteroreceptor complexes in the central nervous system. Curr Protein Pept Sci 15:647–654PubMedCrossRefPubMedCentralGoogle Scholar
  67. Fuxe K, Tarakanov A, Romero Fernandez W et al (2014b) Diversity and bias through receptor-receptor interactions in GPCR heteroreceptor complexes focus on examples from dopamine D2 receptor heteromerization. Front Endocrinol (Lausanne) 5:1–11Google Scholar
  68. Fuxe K, Guidolin D, Agnati LF et al (2015) Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease. Expert Opin Ther Targets 19:377–398PubMedCrossRefPubMedCentralGoogle Scholar
  69. Genedani S, Guidolin D, Leo G et al (2005) Computer-assisted image analysis of caveolin-1 involvement in the internalization process of adenosine A2A-dopamine D2receptor heterodimers. J Mol Neurosci 26:177–184PubMedCrossRefPubMedCentralGoogle Scholar
  70. George SR, Kern A, Smith RG et al (2014) Dopamine receptor heteromeric complexes and their emerging functions. Prog Brain Res 211:183–200PubMedCrossRefPubMedCentralGoogle Scholar
  71. Gines S, Hillion J, Torvinen M et al (2000) Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci 97:8606–8611PubMedCrossRefPubMedCentralGoogle Scholar
  72. Gomes I, Jordan BA, Gupta A et al (2000) Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 20:RC110PubMedPubMedCentralCrossRefGoogle Scholar
  73. Hill SJ, May LT, Kellam B et al (2014) Allosteric interactions at adenosine A(1) and A(3) receptors: new insights into the role of small molecules and receptor dimerization. Br J Pharmacol 171:1102–1113PubMedPubMedCentralCrossRefGoogle Scholar
  74. Hillefors M, Hedlund PB, Euler G (1999) Effects of adenosine A(2A) receptor stimulation in vivo on dopamine D3 receptor agonist binding in the rat brain. Biochem Pharmacol 58:1961–1964PubMedCrossRefPubMedCentralGoogle Scholar
  75. Hillion J, Canals M, Torvinen M et al (2002) Coaggregation cointernalization and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem 277:18091–18097PubMedCrossRefPubMedCentralGoogle Scholar
  76. Hinz S, Navarro G, Borroto-Escuela D et al (2018) Adenosine A2A receptor ligand recognition and signaling is blocked by A2B receptors. Oncotarget 9:13593–13611Google Scholar
  77. Hornykiewicz O (2006) The discovery of dopamine deficiency in the parkinsonian brain. J Neural Transm 9:15Google Scholar
  78. Jaberi E, Rohani M, Shahidi GA et al (2016) Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction. Mov Disord 31:1004–1011PubMedCrossRefPubMedCentralGoogle Scholar
  79. Kachroo A (2005) Interactions between metabotropic glutamate 5 and adenosine A2A receptors in normal and Parkinsonian mice. J Neurosci 25:10414–10419PubMedCrossRefPubMedCentralGoogle Scholar
  80. Kachroo A, Schwarzschild MA (2012) Adenosine A(2A) receptor gene disruption protects in an α-synuclein model of Parkinson’s disease. Ann Neurol 71:278–282PubMedPubMedCentralCrossRefGoogle Scholar
  81. Kieburtz K, Olanow CW (2015) Advances in clinical trials for movement disorders. Mov Disord 30:1580–1587PubMedCrossRefPubMedCentralGoogle Scholar
  82. Kim SK, Jacobson KA (2006) Computational prediction of homodimerization of the A3 adenosine receptor. J Mol Graph Model 25:549–561PubMedCrossRefPubMedCentralGoogle Scholar
  83. Koizumi S, Ohsawa K, Inoue K et al (2013) Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia 61:47–54PubMedCrossRefPubMedCentralGoogle Scholar
  84. Kondo T, Mizuno Y, Japanese Istradefylline Study Group (2015) A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol 38:41–46PubMedCrossRefPubMedCentralGoogle Scholar
  85. Maggio R, Aloisi G, Silvano E et al (2010) Heterodimerization of dopamine receptors: new insights into functional and therapeutic significance. Parkinsonism Relat Disord 15:S2–S7CrossRefGoogle Scholar
  86. Mango D, Bonito-Oliva A, Ledonne A et al (2014) Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. Exp Neurol 261:733–743PubMedCrossRefPubMedCentralGoogle Scholar
  87. Marcellino D, Ferré S, Casadó V et al (2008) Identification of dopamine D1-D3 receptor heteromers: indications for a role of synergistic D1-D3 receptor interactions in the striatum. J Biol Chem 283:26016–26025PubMedPubMedCentralCrossRefGoogle Scholar
  88. Márquez-Gómez R, Robins MT, Gutiérrez-Rodelo C et al (2018) Functional histamine H 3 and adenosine A2A receptor heteromers in recombinant cells and rat striatum. Pharmacol Res 129:515–525Google Scholar
  89. May LT, Bridge LJ, Stoddart L et al (2011) Allosteric interactions across native adenosine-A3 receptor homodimers: quantification using single-cell ligand-binding kinetics. FASEB J 25:3465–3476PubMedPubMedCentralCrossRefGoogle Scholar
  90. Melani A, Dettori I, Corti F et al (2015) Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia. Neurol Sci 36:1441–1448PubMedCrossRefPubMedCentralGoogle Scholar
  91. Mirabet M, Mallol J, Lluis C et al (1997) Calcium mobilization in Jurkat cells via A(2b) adenosine receptors. Br J Pharmacol 122:1075–1082PubMedPubMedCentralCrossRefGoogle Scholar
  92. Mizuno N, Suzuki T, Hirasawa N et al (2012) Hetero-oligomerization between adenosine A1 and thromboxane A2 receptors and cellular signal transduction on stimulation with high and low concentrations of agonists for both receptors. Eur J Pharmacol 677:5–14PubMedCrossRefPubMedCentralGoogle Scholar
  93. Mizuno N, Suzuki T, Kishimoto Y et al (2013a) Biochemical assay of G protein-coupled receptor oligomerization: adenosine A1 and thromboxane A2 receptors form the novel functional hetero-oligomer. Methods Cell Biol 117:213–227PubMedCrossRefPubMedCentralGoogle Scholar
  94. Mizuno Y, Kondo T, Japanese Istradefylline Study Group (2013b) Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson’s disease. Mov Disord 28:1138–1141PubMedPubMedCentralCrossRefGoogle Scholar
  95. Morelli M, Paolo T, Di Wardas J et al (2007) Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog Neurobiol 83:293–309PubMedCrossRefPubMedCentralGoogle Scholar
  96. Moriyama K, Sitkovsky MV (2010) Adenosine A2A receptor is involved in cell surface expression of A2B receptor. J Biol Chem 285:39271–39288PubMedPubMedCentralCrossRefGoogle Scholar
  97. Muñoz LM, Lucas P, Navarro G et al (2009) Dynamic regulation of CXCR1 and CXCR2 homo- and heterodimers. J Immunol 183:7337–7346CrossRefGoogle Scholar
  98. Muñoz LM, Lucas P, Holgado BL et al (2011) Receptor oligomerization: a pivotal mechanism for regulating chemokine function. Pharmacol Ther 131:351–358PubMedCrossRefPubMedCentralGoogle Scholar
  99. Muñoz LM, Holgado BL, Martínez AC et al (2012) Chemokine receptor oligomerization: a further step toward chemokine function. Immunol Lett 145:23–29PubMedCrossRefPubMedCentralGoogle Scholar
  100. Nakata H, Suzuki T, Namba K et al (2010) Dimerization of G protein-coupled purinergic receptors: increasing the diversity of purinergic receptor signal responses and receptor functions. J Recept Signal Transduction 30:337–346CrossRefGoogle Scholar
  101. Navarro G, Carriba P, Gandía J et al (2008) Detection of heteromers formed by cannabinoid CB1 dopamine D2 and adenosine A2A G-protein-coupled receptors by combining bimolecular fluorescence complementation and bioluminescence energy transfer. Sci World J 8:1088–1097CrossRefGoogle Scholar
  102. Navarro G, Aymerich MS, Marcellino D et al (2009) Interactions between calmodulin adenosine A2A and dopamine D2 receptors. J Biol Chem 284:28058–28068PubMedPubMedCentralCrossRefGoogle Scholar
  103. Navarro G, Ferre S, Cordomi A et al (2010) Interactions between intracellular domains as key determinants of the quaternary structure and function of receptor heteromers. J Biol Chem 285:27346–27359PubMedPubMedCentralCrossRefGoogle Scholar
  104. Navarro G, Borroto-Escuela DO, Fuxe K et al (2016a) Purinergic signaling in Parkinson’s disease relevance for treatment. Neuropharmacology 104:161–168PubMedCrossRefPubMedCentralGoogle Scholar
  105. Navarro G, Cordomí A, Zelman-Femiak M et al (2016b) Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs. BMC Biol 14:26PubMedPubMedCentralCrossRefGoogle Scholar
  106. Navarro G, Borroto-Escuela D, Angelats E et al (2017) Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia relevance for Alzheimer’s disease and levo-dopa-induced dyskinesia. Brain Behav Immun 67:139–151Google Scholar
  107. Navarro G, Cordomí A, Brugarolas M et al (2018) Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain. BMC Biol 16:24Google Scholar
  108. Nishi A, Liu F, Matsuyama S et al (2003) Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. Proc Natl Acad Sci U S A 100:1322–1327PubMedPubMedCentralCrossRefGoogle Scholar
  109. Noble F, Cox BM (1995) Differential regulation of D1 dopamine receptor and of A2A Adenosine receptor stimulated adenylyl cyclase by mu- delta 1- and delta 2 opioid agonists in rat caudate putamen. J Neurochem 65:125–133PubMedCrossRefPubMedCentralGoogle Scholar
  110. Olanow CW, Agid Y, Mizuno Y et al (2004) Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord 19:997–1005PubMedCrossRefPubMedCentralGoogle Scholar
  111. Olanow CW, Kieburtz K, Katz R (2017) Clinical approaches to the development of a neuroprotective therapy for PD. Exp Neurol 298:246–251PubMedCrossRefPubMedCentralGoogle Scholar
  112. Orru M, Bakešová J, Brugarolas M et al (2011) Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists. PLoS One 6:e16088Google Scholar
  113. Pedata F, Dettori I, Coppi E et al (2016) Purinergic signalling in brain ischemia. Neuropharmacology 104:105–130PubMedCrossRefPubMedCentralGoogle Scholar
  114. Perreault ML, Hasbi A, O’dowd BF et al (2014) Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology 39:156–168PubMedCrossRefPubMedCentralGoogle Scholar
  115. Pinna A, Wardas J, Cristalli G et al (1997) Adenosine A(2A) receptor agonists increase Fos-like immunoreactivity in mesolimbic areas. Brain Res 759:41–49PubMedCrossRefPubMedCentralGoogle Scholar
  116. Pinna A, Pontis S, Borsini F et al (2007) Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson’s disease. Synapse 61:606–614PubMedCrossRefPubMedCentralGoogle Scholar
  117. Pinna A, Bonaventura J, Farré D et al (2014a) L-DOPA disrupts adenosine A2A-cannabinoid CB-1-dopamine D-2 receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: biochemical and behavioral studies. Exp Neurol 253:180–191PubMedCrossRefPubMedCentralGoogle Scholar
  118. Pinna A, Bonaventura J, Farré D et al (2014b) l-DOPA disrupts adenosine A2A–cannabinoid CB1–dopamine D2 receptor heteromer cross-talk in the striatum of hemiparkinsonian rats: biochemical and behavioral studies. Exp Neurol 253:180–191PubMedCrossRefPubMedCentralGoogle Scholar
  119. Rashid AJ, So CH, Kong MMC et al (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci U S A 104:654–659PubMedCrossRefPubMedCentralGoogle Scholar
  120. Rimondini R, Ferré S, Ogren SO et al (1997) Adenosine A2A agonists: a potential new type of atypical antipsychotic. Neuropsychopharmacology 17:82–91PubMedCrossRefPubMedCentralGoogle Scholar
  121. Saki M, Yamada K, Koshimura E et al (2013) In vitro pharmacological profile of the A2A receptor antagonist istradefylline. Naunyn Schmiedeberg's Arch Pharmacol 386:963–972CrossRefGoogle Scholar
  122. Santana N, Bortolozzi A, Serrats J et al (2004) Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 14:1100–1109PubMedCrossRefPubMedCentralGoogle Scholar
  123. Schicker K, Hussl S, Chandaka GK et al (2009) A membrane network of receptors and enzymes for adenine nucleotides and nucleosides. Biochim Biophys Acta 1793:325–334PubMedCrossRefPubMedCentralGoogle Scholar
  124. Schwarzschild MA, Chen JF, Ascherio A (2002) Caffeinated clues and the promise of adenosine A(2A) antagonists in PD. Neurology 58:1154–1160PubMedCrossRefPubMedCentralGoogle Scholar
  125. Schwarzschild MA, Agnati L, Fuxe K et al (2006) Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci 29:647–654PubMedCrossRefPubMedCentralGoogle Scholar
  126. Shen JJ, Zhang L, Song W et al (2013) Design synthesis and biological evaluation of bivalent ligands against A(1)-D(1) receptor heteromers. Acta Pharmacol Sin 34:441–452PubMedPubMedCentralCrossRefGoogle Scholar
  127. Shewan D, Dwivedy A, Anderson R et al (2002) Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway. Nat Neurosci 5:955–962PubMedCrossRefPubMedCentralGoogle Scholar
  128. Short JL, Ledent C, Borrelli E et al (2006) Genetic interdependence of adenosine and dopamine receptors: evidence from receptor knockout mice. Neuroscience 139:661–670PubMedCrossRefPubMedCentralGoogle Scholar
  129. Simola N, Morelli M, Pinna A (2008) Adenosine A2A receptor antagonists and Parkinson’s disease: state of the art and future directions. Curr Pharm Des 14:1475–1489PubMedCrossRefPubMedCentralGoogle Scholar
  130. Soriano A, Ventura R, Molero A et al (2009) Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A/ D2receptor heteromers. J Med Chem 52:5590–5602PubMedCrossRefPubMedCentralGoogle Scholar
  131. Springael JY, Urizar E, Parmentier M (2005) Dimerization of chemokine receptors and its functional consequences. Cytokine Growth Factor Rev 16:611–623PubMedCrossRefPubMedCentralGoogle Scholar
  132. Strömberg I, Popoli P, Müller CE et al (2000) Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum. Eur J Neurosci 12:4033–4037PubMedCrossRefPubMedCentralGoogle Scholar
  133. Suzuki T, Namba K, Tsuga H et al (2006) Regulation of pharmacology by hetero-oligomerization between A1 adenosine receptor and P2Y2 receptor. Biochem Biophys Res Commun 351:559–565PubMedCrossRefPubMedCentralGoogle Scholar
  134. Suzuki T, Namba K, Mizuno N et al (2013) Hetero-oligomerization and specificity changes of G protein-coupled purinergic receptors: novel insight into diversification of signal transduction. Methods Enzymol 521:239–257PubMedCrossRefPubMedCentralGoogle Scholar
  135. Tanganelli S, Sandager Nielsen K, Ferraro L 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 10:273–280PubMedCrossRefPubMedCentralGoogle Scholar
  136. Tonazzini I, Trincavelli ML, Storm-Mathisen J et al (2007) Co-localization and functional cross-talk between A1 and P2Y1 purine receptors in rat hippocampus. Eur J Neurosci 26:890–902PubMedPubMedCentralCrossRefGoogle Scholar
  137. Torvinen M, Ginés S, Hillion J et al (2002) Interactions among adenosine deaminase adenosine A1 receptors and dopamine D1 receptors in stably cotransfected fibroblast cells and neurons. Neuroscience 113:709–719PubMedCrossRefPubMedCentralGoogle Scholar
  138. Torvinen M, Marcellino D, Canals M et al (2005) Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. Mol Pharmacol 67:400–407PubMedCrossRefPubMedCentralGoogle Scholar
  139. Vendrell M, Angulo E, Casadó V et al (2007) Novel ergopeptides as dual ligands for adenosine and dopamine receptors. J Med Chem 50:3062–3069PubMedCrossRefPubMedCentralGoogle Scholar
  140. Wardas J (2008) Potential role of adenosine A2A receptors in the treatment of schizophrenia. Front Biosci 13:4071–4096PubMedCrossRefPubMedCentralGoogle Scholar
  141. Woods AS, Marcellino D, Jackson SN et al (2008) How calmodulin interacts with the adenosine A2A and the dopamine D2 receptors. J Proteome Res 7:3428–3434PubMedPubMedCentralCrossRefGoogle Scholar
  142. Woods LT, Ajit D, Camden JM et al (2016) Purinergic receptors as potential therapeutic targets in Alzheimer’s disease. Neuropharmacology 104:169–179PubMedCrossRefPubMedCentralGoogle Scholar
  143. Xiao D, Cassin JJ, Healy B et al (2011) Deletion of adenosine A1 or A2A receptors reduces l-34-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson’s disease. Brain Res 1367:310–318PubMedCrossRefPubMedCentralGoogle Scholar
  144. Yoshioka K, Saitoh O, Nakata H (2001) Heteromeric association creates a P2Y-like adenosine receptor. Proc Natl Acad Sci U S A 98:7617–7622PubMedPubMedCentralCrossRefGoogle Scholar
  145. Yoshioka K, Hosoda R, Kuroda Y et al (2002a) Hetero-oligomerization of adenosine A1 receptors with P2Y1 receptors in rat brains. FEBS Lett 531:299–303PubMedCrossRefPubMedCentralGoogle Scholar
  146. Yoshioka K, Saitoh O, Nakata H (2002b) Agonist-promoted heteromeric oligomerization between adenosine A(1) and P2Y(1) receptors in living cells. FEBS Lett 523:147–151PubMedCrossRefPubMedCentralGoogle Scholar
  147. Zoli M, Agnati LF, Hedlund PB et al (1993) Receptor-receptor interactions as an integrative mechanism in nerve cells. Mol Neurobiol 7:293–334PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Gemma Navarro
    • 1
    • 2
  • Dasiel O. Borroto-Escuela
    • 3
  • Kiell Fuxe
    • 3
  • Rafael Franco
    • 2
    • 4
  1. 1.Department of Biochemistry and Physiology, Faculty of PharmacyUniversity of BarcelonaBarcelonaSpain
  2. 2.Centro de Investigación en Red sobre Enfermedades Neurodegenerativas. CIBERNED. Instituto de Salud Carlos IIIMadridSpain
  3. 3.Department of NeuroscienceKarolinska InstitutetStockholmSweden
  4. 4.Department of Biochemistry and Molecular Biomedicine, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain

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