Neurobiology of Aging
Volume 29, Issue 3 , Pages 379-396 , March 2008

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

  • E.R. Bychkov

      Affiliations

    • Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    • Laboratory of Neuroimmunology, Institute of Human Brain, St. Petersburg 197376, Russia
  • ,
  • V.V. Gurevich

      Affiliations

    • Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
  • ,
  • J.N. Joyce

      Affiliations

    • Parkinson's Disease Research Center, Sun Health Research Institute, Sun City, AZ 85351, USA
  • ,
  • J.L. Benovic

      Affiliations

    • Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
  • ,
  • E.V. Gurevich

      Affiliations

    • Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    • Corresponding Author InformationCorresponding author at: Department of Pharmacology, Vanderbilt University Medical Center, Preston Research Building Room 422, Nashville, TN 37232, United States. Tel.: +1 615 936 2720; fax: +1 615 343 6532.

Received 13 June 2006 ,Revised 4 September 2006 ,Accepted 11 October 2006.

References 

  1. Aarsland D, Perry R, Brown A, Larsen JP, Ballard C. Neuropathology of dementia in Parkinson's disease: a prospective, community-based study. Ann. Neurol. 2005;58:773–776
  2. Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ. Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference. Proc. Natl. Acad Sci. U.S.A. 2003;100:1740–1744
  3. Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later-developing dementia and loss of the levodopa response. Arch. Neurol. 2002;59:102–112
  4. Arriza JL, Dawson TM, Simerly RB, Martin LJ, Caron MG, Snyder SH, et al. The G-protein-coupled receptor kinases bARK1 and bARK2 are widely distributed at synapses in rat brain. J. Neurosci. 1992;12:4045–4055
  5. Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, et al. Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J. Biol. Chem. 1992;267:17882–17890
  6. Bawa T, Altememi GF, Eikenburg DC, Standifer KM. Desensitization of alpha 2A-adrenoceptor signaling by modest levels of adrenaline is facilitated by beta 2-adrenoceptor-dependent GRK3 up-regulation. Br. J. Pharmacol. 2003;138:921–931
  7. Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. U.S.A. 2004;101:5099–5104
  8. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–273
  9. Benovic JL, Gomez J. Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family. J. Biol. Chem. 1993;268:19521–19527
  10. Bezard E, Gross CE. Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach. Prog. Neurobiol. 1998;55:93–116
  11. Bezard E, Gross CE, Brotchie JM. Presymptomatic compensation in Parkinson's disease is not dopamine-mediated. Trends Neurosci. 2003;26:215–221
  12. Bezard E, Gross CE, Qin L, Gurevich VV, Benovic JL, Gurevich EV. L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiol. Dis. 2005;18:323–335
  13. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin2. Science. 1999;286:2495–2498
  14. Boller F, Mizutani T, Roessmann U, Gambetti P. Parkinson disease, dementia, and Alzheimer disease: clinicopathological correlations. Ann. Neurol. 1980;7:329–335
  15. Bonelli SB, Ransmayr G, Steffelbauer M, Lukas T, Lampl C, Deibl M. L-dopa responsiveness in dementia with Lewy bodies, Parkinson disease with and without dementia. Neurology. 2004;63:376–378
  16. Braak H, Braak E, Yilmazer D, De Vos RAI, Jansen ENH, Bohl J. New aspects of pathology in Parkinson's disease with concomitant incipient Alzheimer's disease. J. Neural. Transm. 1996;(Suppl. 48):1–6
  17. Braak H, Braak E. Staging of Alzheimer-related cortical destruction. Int. Psychogeriatr. 1997;9(Suppl. 1):257–261
  18. Burn DJ, Rowan EN, Minett T, Sanders J, Myint P, Richardson J, et al. Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: a cross-sectional comparative stud. Mov. Disord. 2003;18:884–889
  19. Carman CV, Som T, Kim CM, Benovic JL. Binding and phosphorylation of tubulin by G protein-coupled receptor kinases. J. Biol. Chem. 1998;273:20308–20316
  20. Colloby SJ, Williams ED, Burn DJ, Lloyd JJ, McKeith IG, O’Brien JT. Progression of dopaminergic degeneration in dementia with Lewy bodies and Parkinson's disease with and without dementia assessed using 123I-FP-CIT SPECT. Eur. J. Nucl. Med. Mol. Imaging. 2005;32:1176–1185
  21. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease . Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol. Aging. 1997;18:S1–S2
  22. Diaz A, Pazos A, Florez J, Ayesta FJ, Santana V, Hurle MA. Regulation of mu-opioid receptors, G-protein-coupled receptor kinases and beta-arrestin 2 in the rat brain after chronic opioid receptor antagonism. Neuroscience. 2002;112:345–353
  23. e Lau LM, Schipper CM, Hofman A, Koudstaal PJ, Breteler MM. Prognosis of Parkinson disease: risk of dementia and mortality: the Rotterdam Study. Arch. Neurol. 2005;62:1265–1269
  24. Emre M. Dementia associated with Parkinson's disease. Lancet. 2003;2:229–237
  25. Fan X, Zhang J, Zhang X, Yue W, Ma L. Acute and chronic morphine treatments and morphine withdrawal differentially regulate GRK2 and GRK5 gene expression in rat brain. Neuropharmacology. 2002;43:809–816
  26. Gainetdinov RR, Bohn LM, Walker JK, Laporte SA, Macrae AD, Caron MG, et al. Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron. 1999;24:1029–1036
  27. Gainetdinov RR, Bohn LM, Sotnikova TD, Cyr M, Laakso A, Macrae AD, et al. Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice. Neuron. 2003;38:291–303
  28. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch. Neurol. 1999;56:33–39
  29. Grange-Midroit M, Garcia-Sevilla JA, Ferrer-Alcon M, La Harpe R, Huguelet P, Guimon J. Regulation of GRK 2 and 6, beta-arrestin-2 and associated proteins in the prefrontal cortex of drug-free and antidepressant drug-treated subjects with major depression. Brain Res. Mol. Brain Res. 2003;111:31–41
  30. Guigoni C, Aubert I, Li Q, Gurevich VV, Benovic JL, Ferry S, et al. Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat. Disord. 2005;11(Suppl. 1):S25–S29
  31. Gurevich EV, Benovic JL, Gurevich VV. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience. 2002;109:421–436
  32. Gurevich EV, Benovic JL, Gurevich VV. Arrestin2 expression selectively increases during neural differentiation. J. Neurochem. 2004;91:1404–1416
  33. Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim CM, Sterne-Marr R, et al. Arrestin interaction with G protein-coupled receptors. Direct binding studies of wild type and mutant arrestins with rhodopsin, b2-adrenergic, and m2 muscarinic cholinergic receptors. J. Biol. Chem. 1995;270:720–731
  34. Gurevich VV, Gurevich EV. The new face of active receptor bound arrestin attracts new partners. Structure. 2003;11:1037–1042
  35. Gurevich VV, Gurevich EV. The molecular acrobatics of arrestin activation. TIPS. 2004;25:59–112
  36. Gurevich VV, Gurevich EV. Structural basis of arrestin regulation of G protein-coupled receptors. Pharmacol. Ther. 2006;110:465–502
  37. Hall RA, Lefkowitz RJ. Regulation of G protein-coupled receptor signaling by scaffold proteins. Circ. Res. 2002;91:672–680
  38. Hanson SM, Francis DJ, Vishnivetskiy SA, Klug CS, Gurevich VV. Visual arrestin binding to microtubules involves a distinct conformational change. J. Biol. Chem. 2006;281:9765–9772
  39. Hanson SM, Francis DJ, Vishnivetskiy SA, Raman D, Van Eps N, Hubbell WL, et al. Arrestin binding to microtubules involves a distinct conformational change. FASEB J. 2006;20:A110–A1110
  40. Hilker R, Thomas AV, Klein JC, Weisenbach S, Kalbe E, Burghaus L, et al. Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005;65:1716–1722
  41. Horie K, Insel PA. Retrovirally mediated transfer of a G protein-coupled receptor kinase (GRK) dominant-negative mutant enhances endogenous calcitonin receptor signaling in chinese hamster ovary cells. GRK inhibition enhances expression of receptors and receptor mRNA. J. Biol. Chem. 2000;275:29433–29440
  42. Hurle MA. Changes in the expression of G protein-coupled receptor kinases and beta-arrestin 2 in rat brain during opioid tolerance and supersensitivity. J. Neurochem. 2001;77:486–492
  43. Hurtig HI, Trojanowski JQ, Galvin J, Ewbank D, Schmidt ML, Lee VM, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson's disease. Neurology. 2000;54:1916–1921
  44. Iaccarino G, Rockman HA, Shotwell KF, Tomhave ED, Koch WJ. Myocardial overexpression of GRK3 in transgenic mice: evidence for in vivo selectivity of GRKs. Am. J. Physiol. 1998;275:1298–1306
  45. Iaccarino G, Tomhave ED, Lefkowitz RJ, Koch WJ. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by b-adrenergic receptor stimulation and blockade. Circulation. 1998;98:1783–1789
  46. Iaccarino G, Lefkowitz RJ, Koch WJ. Myocardial G protein-coupled receptor kinases: implications for heart failure therapy. Proc. Assoc. Am. Phys. 1999;111:399–405
  47. Ito K, Nagano-Saito A, Kato T, Arahata Y, Nakamura A, Kawasumi Y, et al. Striatal and extrastriatal dysfunction in Parkinson's disease with dementia: a 6-[18F]fluoro-L-dopa PET study. Brain. 2002;125:1358–1365
  48. Jellinger KA. Morphological substrates of dementia in parkinsonism. A critical update. J. Neural. Transm. 1997;51:57–82
  49. Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J. Neural. Transm. 2002;109:329–339
  50. Joyce JN, Ryoo H, Gurevich EV, Adler C, Beach T. Ventral striatal D(3) receptors and Parkinson's Disease. Parkinsonism Relat. Disord. 2001;7:225–230
  51. Joyce JN, Ryoo HL, Beach TB, Caviness JN, Stacy M, Gurevich EV, et al. Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors. Brain Res. 2002;955:138–152
  52. Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, et al. A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell. 2005;123:833–847
  53. Kim CM, Dion SB, Onorato JJ, Benovic JL. Expression and characterization of two beta-adrenergic receptor kinase isoforms using the baculovirus expression system. Receptor. 1993;3:39–55
  54. Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, et al. Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signalling. Proc. Natl. Acad. Sci. U.S.A. 2005;102:142–1447
  55. Kim KM, Valenzano KJ, Robinson SR, Yao WD, Barak LS, Caron MG. Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J. Biol. Chem. 2001;276:37409–37414
  56. Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, et al. Neuropathology of cognitively normal elderly. J. Neuropathol. Exp. Neurol. 2003;62:1087–1095
  57. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, et al. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995;268:1350–1353
  58. Kohout TA, Lin FS, Perry SJ, Conner DA, Lefkowitz RJ. Beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc. Natl. Acad. Sci. U.S.A. 2001;98:1601–1606
  59. Krupnick JG, Benovic JL. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annu. Rev. Pharmacol. Toxicol. 1998;38:289–319
  60. Kunapuli P, Onorato JJ, Hosey MM, Benovic JL. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK5. J. Biol. Chem. 1994;269:1099–1105
  61. Lefkowitz RJ, Whalen EJ. Beta-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 2004;16:162–168
  62. Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science. 2005;308:512–517
  63. Levy G. Dementia in Parkinson's disease challenges the “gold standard”. Ann. Neurol. 2005;58:663–665
  64. Lieberman A. Depression in Parkinson's disease—a review. Acta Neurol. Scand. 2006;113:1–8
  65. Loudon RP, Benovic JL. Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6. J. Biol. Chem. 1994;269:22691–22697
  66. Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. U.S.A. 2001;98:2449–2454
  67. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson's disease dementia. Cochrane Database Syst. Rev. 2006;1:CD004747
  68. Mattila PM, Rinne JO, Helenius H, Dickson DW, Roytta M. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson's disease. Acta Neuropathol. 2000;100:285–290
  69. McDonald WM, Holtzheimer PEr , Byrd EH. The diagnosis and treatment of depression in Parkinson's disease. Curr. Treat Opinions Neurol. 2006;8:245–255
  70. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996;47:1113–1124
  71. Ménard L, Ferguson SS, Barak LS, Bertrand L, Premont RT, Colapietro AM, et al. Members of the G protein-coupled receptor kinase family that phosphorylate the β2-adrenergic receptor facilitate sequestration. Biochemistry. 1996;35:4155–4160
  72. Miralles A, Asensio VJ, Garcia-Sevilla JA. Acute treatment with the cyclic antidepressant desipramine, but not fluoxetine, increases membrane-associated G protein-coupled receptor kinases 2/3 in rat brain. Neuropharmacology. 2002;43:1249–1257
  73. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991;41:479–486
  74. Mundell SJ, Luty JS, Willets J, Benovic JL, Kelly E. Enhanced expression of G protein-coupled receptor kinase 2 selectively increases the sensitivity of A2A adenosine receptors to agonist-induced desensitization. Br. J. Pharmacol. 1998;125:347–356
  75. Mundell SJ, Loudon RP, Benovic JL. Characterization of G protein-coupled receptor regulation in antisense mRNA-expressing cells with reduced arrestin levels. Biochemistry. 1999;38:8723–8732
  76. Muriel MP, Bernard V, Levey AI, Laribi O, Abrous DN, Agid Y, et al. Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson's disease. Ann. Neurol. 1999;46:103–111
  77. Nair KS, Hanson SM, Mendez A, Gurevich EV, Kennedy MJ, Shestopalov VI, et al. Light-dependent redistribution of arrestin in vertebrate rods is an energy-independent process governed by protein-protein interactions. Neuron. 2005;46:555–567
  78. Oakley RH, Laporte SA, Holt JA, Caron MG, Barak LS. Differential affinities of visual arrestin, barrestin1, and barrestin2 for G protein-coupled receptors delineate two major classes of receptors. J. Biol. Chem. 2000;275:17201–17210
  79. Orsini MJ, Benovic JL. Characterization of dominant negative arrestins that inhibit beta-2-adrenergic receptor internalization by distinct mechanisms. J. Biol. Chem. 1998;273:34616–34622
  80. Ozaita A, Escriba PV, Ventayol P, Murga C, Mayor FJ, Garcia-Sevilla JA. Regulation of G protein-coupled receptor kinase 2 in brains of opiate-treated rats and human opiate addicts. J. Neurochem. 1998;1249–1257
  81. Pan L, Gurevich EV, Gurevich VV. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor. J. Biol. Chem. 2003;278:11623–11632
  82. Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I. Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann. Neurol. 2005;57:82–91
  83. Parruti G, Peracchia F, Sallese M, Ambrosini G, Masini M, Rotilio D, et al. Molecular analysis of human beta-arrestin-1: cloning, tissue distribution, and regulation of expression, Identification of two isoforms generated by alternative splicing. J. Biol. Chem. 1993;268:9753–9761
  84. Penela P, Elorza A, Sarnago S, Mayor FJ. Beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. EMBO J. 2001;20:5129–5138
  85. Penela P, Ribas C, Mayor FJ. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 2003;15:973–981
  86. Penela P, Murga C, Ribas C, Tutor AS, Peregrin S, Mayor FJ. Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease. Cardiovasc. Res. 2006;69:46–56
  87. Pierce K, Luttrell LM, Lefkowitz RJ. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene. 2001;20:1532–1539
  88. Poewe W. Treatment of dementia with Lewy bodies and Parkinson's disease dementia. Mov. Disord. 2005;20:S77–S82
  89. Premont RT, Koch WJ, Inglese J, Lefkowitz RJ. Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases. J. Biol. Chem. 1994;269:6832–6841
  90. Pronin AN, Morris AJ, Surguchov A, Benovic JL. Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J. Biol. Chem. 2000;275:26515–26522
  91. Ramos-Ruiz R, Penela P, Penn RB, Mayor FJ. Analysis of the human G protein-coupled receptor kinase 2 (GRK2) gene promoter: regulation by signal transduction systems in aortic smooth muscle cells. Circulation. 2000;101:2083–2089
  92. Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc. Natl. Acad. Sci. U.S.A. 2005;102:1448–1453
  93. Richard IH, Papka M, Rubio A, Kurlan R. Parkinson's disease and dementia with Lewy bodies: one disease or two?. Mov. Disord. 2002;17:1161–1165
  94. Richardson RM, Hosey MM. Agonist-induced phosphorylation and desensitization of human m2 muscarinic cholinergic receptors in Sf9 insect cells. J. Biol. Chem. 1993;267:22249–22255
  95. Rockman HA, Choi DJ, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ. Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 1996;93:9954–9959
  96. Ryoo HL, Pierrotti D, Joyce JN. Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson's disease. Mov. Disord. 1998;13:788–797
  97. Sallese M, Mariggio S, Collodel G, Moretti E, Piomboni P, Baccetti B, et al. G protein-coupled receptor kinase GRK4. Molecular analysis of the four isoforms and ultrastructural localization in spermatozoa and germinal cells. J. Biol. Chem. 1997;272:10188–10195
  98. Sterne-Marr R, Gurevich VV, Goldsmith P, Bodine RC, Sanders C, Donoso LA, et al. Polypeptide variants of beta-arrestin and arrestin3. J. Biol. Chem. 1993;268:15640–15648
  99. Terwilliger RZ, Ortiz J, Guitart X, Nestler EJ. Chronic morphine administration increases beta-adrenergic receptor kinase (beta ARK) levels in the rat locus coeruleus. J. Neurochem. 1994;63:1983–1986
  100. Tohgo A, Pierce KL, Choy EW, Lefkowitz RJ, Luttrell LM. Beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation. J. Biol. Chem. 2002;277:9429–9436
  101. Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, et al. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J. Biol. Chem. 2003;278:6258–6267
  102. Tsuboi Y, Dickson DW. Dementia with Lewy bodies and Parkinson's disease with dementia: are they different?. Parkinsonism Relat. Disord. 2005;11(Suppl. 1):S47–S51
  103. Willets JM, Parent JL, Benovic JL, Kelly E. Selective reduction in A2 adenosine receptor desensitization following antisense-induced suppression of G protein-coupled receptor kinase 2 expression. J. Neurochem. 1999;73:1781–1789

PII: S0197-4580(06)00389-7

doi: 10.1016/j.neurobiolaging.2006.10.012

Neurobiology of Aging
Volume 29, Issue 3 , Pages 379-396 , March 2008