Cholesterol at the Endoplasmic Reticulum: Roles of the Sigma-1 Receptor Chaperone and Implications thereof in Human Diseases

Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 51)

Abstract

Despite substantial data elucidating the roles of cholesterol in lipid rafts at the plasma membrane, the roles of cholesterol and related lipids in lipid raft microdomains at the level of subcellular membrane, such as the endoplasmic reticulum (ER) membrane, remain less understood. Growing evidence, however, begins to unveil the importance of cholesterol and lipids on the lipid raft at the ER membrane. A few ER proteins including the sigma-1 receptor chaperone were identified at lipid raft-like microdomains of the ER membrane. The sigma-1 receptor, which is highly expressed at a subdomain of ER membrane directly apposing mitochondria and known as the mitochondria-associated ER membrane or MAM, has been shown to associate with steroids as well as cholesterol. The sigma-1 receptor has been implicated in ER lipid metabolisms/transports, lipid raft reconstitution at the plasma membrane, trophic factor signalling, cellular differentiation, and cellular protection against β-amyloid-induced neurotoxicity. Recent studies on sigma-1 receptor chaperones and other ER proteins clearly suggest that cholesterol, in concert with those ER proteins, may regulate several important functions of the ER including folding, degradation, compartmentalization, and segregation of ER proteins, and the biosynthesis of sphingolipids.

Keywords

Cholesterol Steroid Sigma-1 receptor chaperone Endoplasmic reticulum Mitochondria-associated ER membrane Lipid raft Detergent-resistant microdomain Trophic factor 

Abbreviations

ER

endoplasmic reticulum

MAM

mitochondria-associated ER membrane

SREBP

sterol regulatory element binding protein

PHB

prohibitin domain-containing

PrP

prion protein

erlin

ER lipid raft protein

IP3 receptors

inositol 1,4,5-trisphosphate receptors

PtSer

phosphatidylserine

PtEt

phosphatidylethanolamine

SBDL

sterol-binding domain-like

IAF

iodo-azido fenpropimorph

NGF

nerve growth factor

EGF

epidermal growth factor

BDNF

brain-derived neurotrophic factor

MAPK

mitogen-activated protein kinase

NMDA

N-methyl-D-aspartate

Hsp

heat shock protein

BiP

immunoglobulin binding protein

References

  1. Achison, M, Boylan, MT., Hupp, TR. and Spruce, BA., 2007, HIF-1alpha contributes to tumour-selective killing by the sigma receptor antagonist rimcazole. Oncogene 26: 1137–1146.CrossRefPubMedGoogle Scholar
  2. Alonso, G, Phan, V, Guillemain, I, Saunier, M, Legrand, A, Anoal, M and Maurice, T, 2000, Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system. Neuroscience 97: 155–170.CrossRefPubMedGoogle Scholar
  3. Aydar, E, Palmer, CP., Klyachko, VA. and Jackson. M.B., 2002, The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron 34: 399–410.CrossRefPubMedGoogle Scholar
  4. Bae, S, Seong, J and Paik, Y, 2001, Cholesterol biosynthesis from lanosterol: molecular cloning, chromosomal localization, functional expression and liver-specific gene regulation of rat sterol delta8-isomerase, a cholesterogenic enzyme with multiple functions. Biochem J 353: 689–699.CrossRefPubMedGoogle Scholar
  5. Barres, BA. and Smith, SJ., 2001, Neurobiology. Cholesterol–making or breaking the synapse. Science 294: 1296–1297.CrossRefPubMedGoogle Scholar
  6. Bengoechea-Alonso, MT. and Ericsson, J, 2007, SREBP in signal transduction: cholesterol metabolism and beyond. Curr Opin Cell Biol 19: 215–222.CrossRefPubMedGoogle Scholar
  7. Bermack, JE. and Debonnel, G, 2007, Effects of OPC-14523, a combined sigma and 5-HT1a ligand, on pre- and post-synaptic 5-HT1a receptors. J Psychopharmacol 21: 85–92.CrossRefPubMedGoogle Scholar
  8. Bionda, C, Portoukalian, J, Schmitt, D, Rodriguez-Lafrasse, C and Ardail, D, 2004, Subcellular compartmentalization of ceramide metabolism: MAM (mitochondria-associated membrane) and/or mitochondria? Biochem J 382: 527–533.CrossRefPubMedGoogle Scholar
  9. Browman, DT., Resek, ME., Zajchowski, LD. and Robbins, SM., 2006, Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. J Cell Sci 119: 3149–3160.CrossRefPubMedGoogle Scholar
  10. Brown, MS. and Goldstein, JL., 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331–340.CrossRefPubMedGoogle Scholar
  11. Campana, V, Sarnataro, D, Fasano, C, Casanova, P, Paladino, S and Zurzolo, C, 2006, Detergent-resistant membrane domains but not the proteasome are involved in the misfolding of a PrP mutant retained in the endoplasmic reticulum. J Cell Sci 119: 433–442.CrossRefPubMedGoogle Scholar
  12. Chen, L, Dai, XN. and Sokabe, M, 2006, Chronic administration of dehydroepiandrosterone sulfate (DHEAS) primes for facilitated induction of long-term potentiation via sigma 1 (sigma1) receptor: optical imaging study in rat hippocampal slices. Neuropharmacology 50: 380–392.CrossRefPubMedGoogle Scholar
  13. Chen, Y, Hajipour, AR., Sievert, MK., Arbabian, M and Ruoho, AE., 2007, Characterization of the cocaine binding site on the sigma-1 receptor. Biochemistry 46: 3532–3542.CrossRefPubMedGoogle Scholar
  14. Duchen, MR., Verkhratsky, A and Muallem, S, 2008, Mitochondria and calcium in health and disease. Cell Calcium 44: 1–5.CrossRefPubMedGoogle Scholar
  15. Dun, Y, Thangaraju, M, Prasad, P, Ganapathy, V and Smith, SB., 2007, Prevention of excitotoxicity in primary retinal ganglion cells by (+)-pentazocine, a sigma receptor-1 specific ligand. Invest Ophthalmol Vis Sci 48: 4785–4794.CrossRefPubMedGoogle Scholar
  16. Fontanilla, D, Hajipour, AR., Pal, A, Chu, UB., Arbabian, M and Ruoho, AE., 2008, Probing the steroid binding domain-like I (SBDLI) of the sigma-1 receptor binding site using N-substituted photoaffinity labels. Biochemistry 47: 7205–7217.CrossRefPubMedGoogle Scholar
  17. Fontanilla, D, Johannessen, M, Hajipour, AR., Cozzi, NV., Jackson, MB. and Ruoho, AE., 2009, The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323: 934–937.CrossRefPubMedGoogle Scholar
  18. Ganapathy, ME., Prasad, PD., Huang, W, Seth, P, Leibach, FH. and Ganapathy, V, 1999, Molecular and ligand-binding characterization of the sigma-receptor in the Jurkat human T lymphocyte cell line. J Pharmacol Exp Ther 289: 251–260.PubMedGoogle Scholar
  19. Gebreselassie, D and Bowen, WD. 2004, Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes. Eur J Pharmacol 493:19–28.CrossRefPubMedGoogle Scholar
  20. Goyagi, T, Goto, S, Bhardwaj, A, Dawson, VL., Hurn, PD. and Kirsch, JR., 2001, Neuroprotective effect of sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production. Stroke 32: 1613–1620.PubMedGoogle Scholar
  21. Hajnoczky, G and Hoek, JB., 2007, Cell signalling. Mitochondrial longevity pathways. Science 315: 607–609.CrossRefPubMedGoogle Scholar
  22. Hanner, M, Moebius, FF., Flandorfer, A, Knaus, HG., Striessnig, J, Kempner, E and Glossmann, H, 1996, Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci USA 93: 8072–8077.CrossRefPubMedGoogle Scholar
  23. Hayashi, T, Rizzuto, R, Hajnoczky, G and Su, TP., 2009, MAM: more than just a housekeeper. Trends Cell Biol 19: 81–88.CrossRefPubMedGoogle Scholar
  24. Hayashi, T and Su, TP., 2003a, Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther 306: 726–733.CrossRefPubMedGoogle Scholar
  25. Hayashi, T and Su, TP., 2003b, Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther 306: 718–725.CrossRefPubMedGoogle Scholar
  26. Hayashi, T and Su, TP., 2004a, Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs 18: 269–284.CrossRefPubMedGoogle Scholar
  27. Hayashi, T and Su, TP., 2004b, Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc Natl Acad Sci U S A 101: 14949–14954.CrossRefPubMedGoogle Scholar
  28. Hayashi, T and Su, TP., 2005, The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: implication for drug abuse. Life Sci 77: 612–1624.CrossRefGoogle Scholar
  29. Hayashi, T and Su, TP., 2007, Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca(2+) Signalling and Cell Survival. Cell 131: 596–610.CrossRefPubMedGoogle Scholar
  30. Hayashi, T and Su, TP., 2008, An update on the development of drugs for neuropsychiatric disorders: focusing on the sigma 1 receptor ligand. Expert Opin Ther Targets 12: 5–58.CrossRefGoogle Scholar
  31. Hoegg, MB., Browman, DT., Resek, ME. and Robbins, SM., 2009, Distinct regions within the erlins are required for oligomerization and association with high molecular weight complexes. J Biol Chem 284: 7766–7776.CrossRefPubMedGoogle Scholar
  32. Hyman, SE., Malenka, RC.and Nestler, EJ., 2006, Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29: 565–598.CrossRefPubMedGoogle Scholar
  33. Ikonen, E and Vainio, S, 2005, Lipid microdomains and insulin resistance: is there a connection? Sci STKE 2005:pe3.Google Scholar
  34. Jiang, G, Mysona, B, Dun, Y, Gnana-Prakasam, JP., Pabla, N, Li, W, Dong, Z, Ganapathy, V and Smith, SB., 2006, Expression, subcellular localization, and regulation of sigma receptor in retinal muller cells. Invest Ophthalmol Vis Sci 47: 5576–5582.CrossRefPubMedGoogle Scholar
  35. Johannessen, MA., Ramachandran, S, Riemer, L, Ramos-Serrano, A, Ruoho, AE. and Jackson, MB., 2009, Voltage-Gated Sodium Channel Modulation by Sigma Receptors in Cardiac Myocytes and Heterologous Systems. Am J Physiol Cell Physiol 296: C1049–C1057.CrossRefPubMedGoogle Scholar
  36. Lajoie, P and Nabi, IR., 2007, Regulation of raft-dependent endocytosis. J Cell Mol Med 11: 644–653.CrossRefPubMedGoogle Scholar
  37. Lavoie, HA. and King, SR., 2009, Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Exp Biol Med (Maywood) 234: 880–907.Google Scholar
  38. Liu, Y, Chen, GD., Lerner, MR., Brackett, DJ. and Matsumoto, RR., 2005, Cocaine up-regulates Fra-2 and sigma-1 receptor gene and protein expression in brain regions involved in addiction and reward. J Pharmacol Exp Ther 314: 770–779.CrossRefPubMedGoogle Scholar
  39. Liu, Y and Matsumoto, RR., 2008, Alterations in fos-related antigen 2 and sigma1 receptor gene and protein expression are associated with the development of cocaine-induced behavioral sensitization: time course and regional distribution studies. J Pharmacol Exp Ther 327: 87–195.Google Scholar
  40. Malorni, W, Giammarioli, AM., Garofalo, T and Sorice, M, 2007, Dynamics of lipid raft components during lymphocyte apoptosis: the paradigmatic role of GD3. Apoptosis 12: 941–949.CrossRefPubMedGoogle Scholar
  41. Marrazzo, A, Caraci, F, Salinaro, ET., Su, TP., Copani, A and Ronsisvalle, G, 2005, Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport 16: 1223–1226.CrossRefPubMedGoogle Scholar
  42. Martin-Fardon, R, Maurice, T, Aujla, H, Bowen, WD. and Weiss, F, 2007, Differential effects of sigma1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs natural reward. Neuropsychopharmacology 32: 1967–1973.CrossRefPubMedGoogle Scholar
  43. Martina, M, Turcotte, ME., Halman, S and Bergeron, R, 2007, The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. J Physiol 578: 143–157.CrossRefPubMedGoogle Scholar
  44. Matsumoto, RR., Liu, Y, Lerner, M, Howard, EW. and Brackett, DJ., 2003, Sigma receptors: potential medications development target for anti-cocaine agents. Eur J Pharmacol 469: 1–12.CrossRefPubMedGoogle Scholar
  45. Maurice, T, 2004, Neurosteroids and sigma1 receptors, biochemical and behavioral relevance. Pharmacopsychiatry 37 Suppl 3: S171–S182.CrossRefPubMedGoogle Scholar
  46. Maurice, T, Martin-Fardon, R, Romieu, P and Matsumoto, RR., 2002, Sigma(1) (sigma(1)) receptor antagonists represent a new strategy against cocaine addiction and toxicity. Neurosci Biobehav Rev 26: 499–527.CrossRefPubMedGoogle Scholar
  47. Mei, J and Pasternak, GW., 2007, Modulation of brainstem opiate analgesia in the rat by sigma 1 receptors: a microinjection study. J Pharmacol Exp Ther 322: 1278–1285.CrossRefPubMedGoogle Scholar
  48. Miljan, EA., Meuillet, EJ., Mania-Farnell, B, George, D, Yamamoto, H, Simon, HG. and Bremer, EG., 2002, Interaction of the extracellular domain of the epidermal growth factor receptor with gangliosides. J Biol Chem 277: 10108–10113.CrossRefPubMedGoogle Scholar
  49. Moebius, FF., Reiter, RJ., Hanner, M and Glossmann, H, 1997, High affinity of sigma 1-binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8-C7 isomerase. Br J Pharmacol 121: 1–6.CrossRefPubMedGoogle Scholar
  50. Nakazawa, M, Matsuno, K and Mita, S, 1998, Activation of sigma1 receptor subtype leads to neuroprotection in the rat primary neuronal cultures. Neurochem Int 32: 337–343.CrossRefPubMedGoogle Scholar
  51. Pal, A, Chu, UB., Ramachandran, S, Grawoig, D, Guo, LW., Hajipour, AR. and Ruoho, AE., 2008, Juxtaposition of the steroid binding domain-like I and II regions constitutes a ligand binding site in the sigma-1 receptor. J Biol Chem. 283: 19646–19656.CrossRefPubMedGoogle Scholar
  52. Pal, A, Hajipour, AR., Fontanilla, D, Ramachandran, S, Chu, UB., Mavlyutov, T and Ruoho, AE., 2007, Identification of regions of the sigma-1 receptor ligand binding site using a novel photoprobe. Mol Pharmacol 72: 921–933.CrossRefPubMedGoogle Scholar
  53. Palmer, CP., Mahen, R, Schnell, E, Djamgoz, MB. and Aydar, E, 2007, Sigma-1 receptors bind cholesterol and remodel lipid rafts in breast cancer cell lines. Cancer Res 67: 11166–11175.CrossRefPubMedGoogle Scholar
  54. Pike, LJ., 2003, Lipid rafts: bringing order to chaos. J Lipid Res 44: 655–667.CrossRefPubMedGoogle Scholar
  55. Pregelj, P, 2008, Involvement of cholesterol in the pathogenesis of Alzheimer’s disease: role of statins. Psychiatr Danub 20:162–167.PubMedGoogle Scholar
  56. Renaudo, A, L’Hoste, S, Guizouarn, H, Borgese, F and Soriani, O 2007, Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Cl- channels. J Biol Chem 282: 2259–2267.CrossRefPubMedGoogle Scholar
  57. Rizzuto, R, Pinton, P, Brini, M, Chiesa, A, Filippin, L and Pozzan, T, 1999, Mitochondria as biosensors of calcium microdomains. Cell Calcium 26: 193–199.CrossRefPubMedGoogle Scholar
  58. Rusinol, AE., Chan, EY. and Vance, JE., 1993, Movement of apolipoprotein B into the lumen of microsomes from hepatocytes is disrupted in membranes enriched in phosphatidylmonomethylethanolamine. J Biol Chem 268: 25168–25175.PubMedGoogle Scholar
  59. Rusinol, AE., Cui, Z, Chen, MH. and Vance, JE., 1994, A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins. J Biol Chem 269: 27494–27502.PubMedGoogle Scholar
  60. Sabeti, J and Gruol, DL., 2008, Emergence of NMDAR-independent long-term potentiation at hippocampal CA1 synapses following early adolescent exposure to chronic intermittent ethanol: role for sigma-receptors. Hippocampus 18: 148–168.CrossRefPubMedGoogle Scholar
  61. Sarnataro, D, Campana, V, Paladino, S, Stornaiuolo, M, Nitsch, L and Zurzolo, C, 2004, PrP(C) association with lipid rafts in the early secretory pathway stabilizes its cellular conformation. Mol Biol Cell 15: 4031–4042.CrossRefPubMedGoogle Scholar
  62. Seth, P, Ganapathy, ME., Conway, SJ., Bridges, CD., Smith, SB., Casellas, P and Ganapathy, V, 2001, Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor. Biochim Biophys Acta 1540: 59–67.CrossRefPubMedGoogle Scholar
  63. Simons, K and Ikonen, E, 1997, Functional rafts in cell membranes. Nature 387: 569–572.CrossRefPubMedGoogle Scholar
  64. Simons, K and Toomre, D, 2000, Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1: 1–39.CrossRefGoogle Scholar
  65. Smith, SB., Duplantier, J, Dun, Y, Mysona, B, Roon, P, Martin, PM. and Ganapathy, V, 2008, In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)-pentazocine. Invest Ophthalmol Vis Sci 49: 4154–4161.CrossRefPubMedGoogle Scholar
  66. Spruce, BA., Campbell, LA., McTavish, N, Cooper, MA., Appleyard, MV., O’Neill, M, Howie, J, Samson, J, Watt, S, Murray, K, McLean, D, Leslie, NR., Safrany, ST., Ferguson, MJ., Peters, JA., Prescott, AR., Box, G, Hayes, A, Nutley, B, Raynaud, F, Downes, CP., Lambert, JJ., Thompson, AM. and Eccles, S, 2004, Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo. Cancer Res 64: 4875–4886.CrossRefPubMedGoogle Scholar
  67. Stefanski, R, Justinova, Z, Hayashi, T, Takebayashi, M, Goldberg, SR. and Su, TP., 2004, Sigma1 receptor upregulation after chronic methamphetamine self-administration in rats: a study with yoked controls. Psychopharmacology (Berl) 175: 68–75.CrossRefGoogle Scholar
  68. Su, TP. and Hayashi, T 2003, Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem 10:2073–2080.CrossRefPubMedGoogle Scholar
  69. Su, TP., London, ED. and Jaffe, JH., 1988, Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 240: 219–221.CrossRefPubMedGoogle Scholar
  70. Suzuki, S, Kiyosue, K, Hazama, S, Ogura, A, Kashihara, M, Hara, T, Koshimizu, H and Kojima, M, 2007, Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development. J Neurosci 27: 6417–6427.CrossRefPubMedGoogle Scholar
  71. Takebayashi, M, Hayashi, T and Su, TP., 2002, Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants. J Pharmacol Exp Ther 303: 1227–1237.CrossRefPubMedGoogle Scholar
  72. Takebayashi, M, Hayashi, T and Su, TP., 2004a, A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors. Pharmacopsychiatry 37 Suppl 3: S208–213.CrossRefPubMedGoogle Scholar
  73. Takebayashi, M, Hayashi, T and Su, TP., 2004b, Sigma-1 receptors potentiate epidermal growth factor signalling towards neuritogenesis in PC12 cells: potential relation to lipid raft reconstitution. Synapse 53: 90–103.CrossRefPubMedGoogle Scholar
  74. Tchedre, KT. and Yorio, T, 2008, Sigma-1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation. Invest Ophthalmol Vis Sci. 49: 2577–2588.CrossRefPubMedGoogle Scholar
  75. van Meer, G, 2000, Cellular organelles: how lipids get there, and back. Trends Cell Biol 10: 550–552.CrossRefPubMedGoogle Scholar
  76. van Meer, G and van Genderen, IL., 1994, Intracellular lipid distribution, transport, and sorting. A cell biologist’s need for physicochemical information. Subcell Biochem 23: 1–24.PubMedGoogle Scholar
  77. Vance, JE., 1990, Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265: 7248–7256.PubMedGoogle Scholar
  78. Vilner, BJ., John, CS. and Bowen, WD., 1995, Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res 55: 408–413.PubMedGoogle Scholar
  79. Voelker, DR., 2000, Interorganelle transport of aminoglycerophospholipids. Biochim Biophys Acta 1486: 97–107.PubMedGoogle Scholar
  80. Volz, HP. and Stoll, KD., 2004, Clinical trials with sigma ligands. Pharmacopsychiatry 37 Suppl 3: S214–220.CrossRefPubMedGoogle Scholar
  81. Yagasaki, Y, Numakawa, T, Kumamaru, E, Hayashi, T, Su, TP. and Kunugi, H, 2006, Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signalling for glutamate release. J Biol Chem 281: 12941–12949.CrossRefPubMedGoogle Scholar
  82. Yamamoto, H, Miura, R, Yamamoto, T, Shinohara, K, Watanabe, M, Okuyama, S, Nakazato, A and Nukada, T, 1999, Amino acid residues in the transmembrane domain of the type 1 sigma receptor critical for ligand binding. FEBS Lett 445: 19–22.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug AbuseDepartment of Health and Human Services, National Institutes of HealthBaltimoreUSA

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