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Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

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Abstract

Adenosine A2A receptor (A2AR) is a G protein-coupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A2AR expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A2AR expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A2AR messenger RNA (mRNA) and protein content as well as A2AR-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A2AR expression could be established. Overall, we concluded that striatal A2AR functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A2AR expression.

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References

  1. Olah ME, Stiles GL (1995) Adenosine receptor subtypes: characterization and therapeutic regulation. Annu Rev Pharmacol Toxicol 35:581–606

    Article  CAS  PubMed  Google Scholar 

  2. Dunwiddie V, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    Article  CAS  PubMed  Google Scholar 

  3. Marala RB, Mustafa SJ (1993) Direct evidence for the coupling of A2-adenosine receptor to stimulatory guanine nucleotide-binding-protein in bovine brain striatum. J Pharmacol Exp Ther 266:294–300

    CAS  PubMed  Google Scholar 

  4. Fredholm BB (1995) Purinoceptors in the nervous system. Pharmacol Toxicol 76:228–239

    Article  CAS  PubMed  Google Scholar 

  5. Calon F, Dridi M, Hornykiewicz O, Bédard PJ, Rajput AH, Di Paolo T (2004) Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias. Brain 127:1075–1084. doi:10.1093/brain/awh128

    Article  PubMed  Google Scholar 

  6. Varani K, Vincenzi F, Tosi A, Gessi S, Casetta I, Granieri G, Fazio P, Leung E, Maclennan S, Granieri E, Borea PA (2010) A2A adenosine receptor overexpression and functionality, as well as TNF-{alpha} levels, correlate with motor symptoms in Parkinson's disease. FASEB J 24:587–598. doi:10.1096/fj.09-141044

    Article  CAS  PubMed  Google Scholar 

  7. Mishina M, Ishiwata K, Naganawa M, Kimura Y, Kitamura S, Suzuki M, Hashimoto M, Ishibashi K, Oda K, Sakata M, Hamamoto M, Kobayashi S, Katayama Y, Ishii K (2011) Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients. PLoS ONE 6:e17338

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ (2011) Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 76:1811–1816

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Casetta I, Vincenzi F, Bencivelli D, Corciulo C, Gentile M, Granieri E, Borea PA, Varani K (2014) A(2A) adenosine receptors and Parkinson's disease severity. Acta Neurol Scand 129:276–281. doi:10.1111/ane.12181

    Article  CAS  PubMed  Google Scholar 

  10. MacCollin M, Peterfreund R, MacDonald M, Fink JS, Gusella J (1994) Mapping of a human A2a adenosine receptor (ADORA2) to chromosome 22. Genomics 20:332–333. doi:10.1006/geno.1994.1181

    Article  CAS  PubMed  Google Scholar 

  11. Le F, Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR (1996) Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A. Biochem Biophys Res Commun 223:461–467. doi:10.1006/bbrc.1996.0916

    Article  CAS  PubMed  Google Scholar 

  12. Peterfreund RA, MacCollin M, Gusella J, Fink JS (1996) Characterization and expression of the human A2a adenosine receptor gene. J Neurochem 66:362–368. doi:10.1046/j.1471-4159.1996.66010362.x

    Article  CAS  PubMed  Google Scholar 

  13. Yu L, Frith MC, Suzuki Y, Peterfreund RA, Gearan T, Sugano S, Schwarzschild MA, Weng Z, Fink JS, Chen JF (2004) Characterization of genomic organization of the adenosine A2A receptor gene by molecular and bioinformatics analyses. Brain Res 1000:156–173. doi:10.1016/j.brainres.2003.11.072

    Article  CAS  PubMed  Google Scholar 

  14. St. Hilaire C, Carroll SH, Chen H, Ravid K (2009) Mechanisms of induction of adenosine receptor genes and its functional significance. J Cell Physiol 218:35–44

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Buira SP, Dentesano G, Albasanz JL, Moreno J, Martín M, Ferrer I, Barrachina M (2010) DNA methylation and Yin Yang-1 repress adenosine A2A receptor levels in human brain. J Neurochem 115:283–295. doi:10.1111/j.1471-4159.2010.06928.x

    Article  CAS  PubMed  Google Scholar 

  16. Villar-Menéndez I, Blanch M, Tyebji S, Pereira-Veiga T, Albasanz JL, Martín M, Ferrer I, Pérez-Navarro E, Barrachina M (2013) Increased 5-methylcytosine and decreased 5-hydroxymethylcytosine levels are associated with reduced striatal A2AR levels in Huntington’s disease. Neuromolecular Med 15:295–309. doi:10.1007/s12017-013-8219-0

    Article  PubMed  Google Scholar 

  17. Villar-Menéndez I, Díaz-Sánchez S, Blanch M, Albasanz JL, Pereira-Veiga T, Monje A, Planchat LM, Ferrer I, Martín M, Barrachina M (2014) Reduced striatal adenosine A(2A) receptor levels define a molecular subgroup in schizophrenia. J Psychiatr Res 51:49–59. doi:10.1016/j.jpsychires.2013.12.013

    Article  PubMed  Google Scholar 

  18. Buira SP, Albasanz JL, Dentesano G, Moreno J, Martín M, Ferrer I, Barrachina M (2010) DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. J Neurochem 112:1273–1285. doi:10.1111/j.1471-4159.2009.06538.x

    Article  CAS  PubMed  Google Scholar 

  19. Bell KM, Potkin SG, Carreon D, Plon L (1994) S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl 154:15–18

    Article  CAS  PubMed  Google Scholar 

  20. Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, McCann PP (1996) S-Adenosylmethionine and methylation. FASEB J 10:471–480

    CAS  PubMed  Google Scholar 

  21. Lu SC (2000) S-Adenosylmethionine. Int J Biochem Cell Biol 32:391–395. doi:10.1016/S1357-2725(99)00139-9

    Article  CAS  PubMed  Google Scholar 

  22. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH (1990) Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53:1096–1098

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Barrachina M, Martín M, Ciruela F and Ferrer I (2011) Epigenetic modulation of adenosine A2A receptor: a putative therapeutical tool for the treatment of Parkinson’s disease. In: Finkelstein D (ed) Towards New Therapies for Parkinson's Disease. In Tech, pp 295–312. ISBN: 978-953-307-463-4. doi: 10.5772/16697.

  24. Albasanz JL, Perez S, Barrachina M, Ferrer I, Martín M (2008) Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease. Brain Pathol 18:211–219. doi:10.1111/j.1750-3639.2007.00112.x

    Article  CAS  PubMed  Google Scholar 

  25. Kobayashi K, Nakajima E, Kubo Y, Yasukawa Y, Iwata N (1990) S-adenosyl-L-methionine ameliorates reduced local cerebral glucose utilization following brain ischemia in the rat. Jpn J Pharmacol 52:141–148

    Article  CAS  PubMed  Google Scholar 

  26. Ehrich M, Nelson MR, Stanssens P, Zabeau M, Liloglou T, Xinarianos G, Cantor CR, Field JK, van den Boom D (2005) Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A 102:15785–15790. doi:10.1073/pnas.0507816102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Ferré S, von Euler G, Johansson B, Fredholm BB (1991) Fuxe K (1991) Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes. Proc Natl Acad Sci U S A 88:7238–7241

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  Google Scholar 

  29. Ciruela F, Fernández-Dueñas V, Llorente J, Borroto-Escuela D, Cuffí ML, Carbonell L, Sánchez S, Agnati LF, Fuxe K, Tasca CI (2012) G protein-coupled receptor oligomerization and brain integration: focus on adenosinergic transmission. Brain Res 1476:86–95

    Article  CAS  PubMed  Google Scholar 

  30. Fuxe K, Agnati LF, Jacobsen K, Hillion J, Canals M, Torvinen M, Tinner-Staines B, Staines W, Rosin D, Terasmaa A, Popoli P, Leo G, Vergoni V, Lluis C, Ciruela F, Franco R, Ferré S (2003) Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease. Neurology 61:S19–S23

    Article  CAS  PubMed  Google Scholar 

  31. Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R, Sussman NM, Istradefylline 6002-US-013 Study Group (2008) Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord 23:2177–2185. doi:10.1002/mds.22095

    Article  PubMed  Google Scholar 

  32. LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P, Sussman NM (2008) 6002-US-005 Study Group. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces “off” time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 63:295–302. doi:10.1002/ana.21315

    Article  CAS  PubMed  Google Scholar 

  33. Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, Sussman NM (2008) A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology 70:2233–2240. doi:10.1212/01.wnl.0000313834.22171.17

    Article  CAS  PubMed  Google Scholar 

  34. Factor S, Mark MH, Watts R, Struck L, Mori A, Ballerini R, Sussman NM, Istradefylline 6002-US-007 Study Group (2010) A long-term study of istradefylline in subjects with fluctuating Parkinson's disease. Parkinsonism Relat Disord 16:423–426. doi:10.1016/j.parkreldis.2010.02.014

    Article  PubMed  Google Scholar 

  35. Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M, Japanese Istradefylline Study Group (2010) Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord 25:1437–1443. doi:10.1002/mds.23107

    Article  PubMed  Google Scholar 

  36. Mizuno Y, Kondo T, Japanese Istradefylline Study Group (2013) Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease. Mov Disord 28:1138–1141. doi:10.1002/mds.25418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Pourcher E, Fernandez HH, Stacy M, Mori A, Ballerini R, Chaikin P (2012) Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study. Parkinsonism Relat Disord 18:178–184. doi:10.1016/j.parkreldis.2011.09.023

    Article  PubMed  Google Scholar 

  38. Chen W, Wang H, Wei H, Gu S, Wei H (2013) Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: a meta-analysis. J Neurol Sci 324:21–28. doi:10.1016/j.jns.2012.08.030

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (grant CP08/00095 to MB), Ministerio de Economía y Competitividad (grants SAF2011-24779, Consolider-Ingenio CSD2008-00005 and PCIN-2013-019-C03-03 to FC, and BFU2011-23034 to MM), and La Fundació La Marató de TV3 (grants 090330 to MB, and 092331 to MM). Also supported by the Catalan Institution for Research and Advanced Studies (ICREA Academia-2010) is FC. FN and FC belong to the “Neuropharmacology and Pain” accredited research group (Generalitat de Catalunya, 2009 SGR 232). IVM is the recipient of an IDIBELL predoctoral fellowship.

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital-ICS, Av. Gran Via de L’Hospitalet 199, L’Hospitalet de Llobregat, 08908, Spain

    Izaskun Villar-Menéndez, Isidre Ferrer & Marta Barrachina

  2. Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain

    Fabiana Nuñez, Jaume Taura, Víctor Fernández-Dueñas & Francisco Ciruela

  3. Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias y Tecnologías Químicas, Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha, Ciudad Real, Spain

    Sara Díaz-Sánchez, José Luis Albasanz & Mairena Martín

  4. Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Medicina de Ciudad Real, CRIB, Universidad de Castilla-La Mancha, Ciudad Real, Spain

    José Luis Albasanz & Mairena Martín

  5. Departament de Patologia i Terapèutica Experimental, Universitat de Barcelona, L’Hospitalet de Llobregat, Spain

    Isidre Ferrer

  6. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain

    Isidre Ferrer & Marta Barrachina

  7. Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, IDIBELL, Universitat de Barcelona, c/Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Spain

    Francisco Ciruela

Authors
  1. Izaskun Villar-Menéndez
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  2. Fabiana Nuñez
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  3. Sara Díaz-Sánchez
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  4. José Luis Albasanz
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  5. Jaume Taura
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  6. Víctor Fernández-Dueñas
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  7. Isidre Ferrer
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  8. Mairena Martín
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  9. Francisco Ciruela
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  10. Marta Barrachina
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Corresponding authors

Correspondence to Francisco Ciruela or Marta Barrachina.

Additional information

Fabiana Nuñez and Sara Díaz-Sánchez contributed equally.

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Villar-Menéndez, I., Nuñez, F., Díaz-Sánchez, S. et al. Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation. Purinergic Signalling 10, 523–528 (2014). https://doi.org/10.1007/s11302-014-9417-4

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  • DOI: https://doi.org/10.1007/s11302-014-9417-4

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