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Research progress on neurobiology of neuronal nitric oxide synthase

神经元型一氧化氮合酶的神经生物学研究进展

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Abstract

Neuronal nitric oxide synthase (nNOS) is mainly expressed in neurons, to some extent in astrocytes and neuronal stem cells. The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS, including nNOS-α, nNOS-β, nNOS-μ, nNOS-γ and nNOS-2. Monomer of nNOS is inactive, and dimer is the active form. Dimerization requires tetrahydrobiopterin (BH4), heme and L-arginine binding. Regulation of nNOS expression relies largely on cAMP response element-binding protein (CREB) activity, and nNOS activity is regulated by heat shock protein 90 (HSP90)/HSP70, calmodulin (CaM), phosphorylation and dephosphorylation at Ser847 and Ser1412, and the protein inhibitor of nNOS (PIN). There are primarily 9 nNOS-interacting proteins, including post-synaptic density protein 95 (PSD95), clathrin assembly lymphoid leukemia (CALM), calcium/calmodulindependent protein kinase II alpha (CAMKIIA), Disks large homolog 4 (DLG4), DLG2, 6-phosphofructokinase, muscle type (PFK-M), carboxy-terminal PDZ ligand of nNOS (CAPON) protein, syntrophin and dynein light chain (LC). Among them, PSD95, CAPON and PFK-M are important nNOS adapter proteins in neurons. The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death. nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states, and negatively regulates neurogenesis under physiological and pathological conditions.

摘要

神经元型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)主要表达于神经元, 在星形胶质细胞和神经干细胞中也有一定水平的表达。 不同的mRNA拼接形式产生了nNOS 蛋白的5 种亚型,包括nNOS-α、 nNOS-β、 nNOS-μ、 nNOS-γ 和nNOS-2。 nNOS 单体不具催化活性, 二聚体是其活性形式。 nNOS 单体发生二聚化需要四氢生物蝶呤、 血红素以及L-精氨酸的结合。 nNOS的表达在很大程度上依赖于cAMP反应元件结合蛋白的活化, 其催化活性的调节与热休克蛋白90/ 热休克蛋白70、 钙调节蛋白、 PIN 蛋白, 以及自身Ser847 和Ser1412 位点的磷酸化和脱磷酸化相关。 能与nNOS相互作用的蛋白主要有9 种, 包括突触后密度蛋白95 (post-synaptic density protein 95, PSD95)、 CALM、 CAMKIIA、 DLG4、 DLG2、 PFK-M、 CAPON、 syntrophin 和 dynein 轻链。 其中PSD95、 CAPON 和 PFK-M 是神经元中最重要的nNOS 调节蛋白。 PSD95 与nNOS 的相互作用能介导突触形成, 并参与N- 甲基-D- 天冬氨酸诱导的神经元死亡。 此外, nNOS 来源的一氧化氮还与多种神经病理状态早期突触丢失导致的认知、 运动功能缺陷相关, 并对生理病理的成年神经发生起负调控作用。

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References

  1. Zhou L, Zhu DY. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide 2009, 20: 223–230.

    Article  CAS  PubMed  Google Scholar 

  2. Bredt DS. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 1999, 31: 577–596.

    Article  CAS  PubMed  Google Scholar 

  3. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthase: structure, function and inhibition. Biochem J 2001, 357: 593–615.

    Article  CAS  PubMed  Google Scholar 

  4. Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007, 8: 766–775.

    Article  CAS  PubMed  Google Scholar 

  5. Wang Y, Newton DC, Robb GB, Kau CL, Miller TL, Cheung AH, et al. RNA diversity has profound effects on the translation of neuronal nitric oxide synthase. Proc Natl Acad Sci U S A 1999, 96: 12150–12155.

    Article  CAS  PubMed  Google Scholar 

  6. Boissel JP, Zelenka M, Godtel-Armbrust U, Feuerstein TJ, Forstermann U. Transcription of different exons 1 of the human neuronal nitric oxide synthase gene is dynamically regulated in a cell- and stimulus-specific manner. Biol Chem 2003, 384: 351–362.

    Article  CAS  PubMed  Google Scholar 

  7. Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 1988, 336: 385–388.

    Article  CAS  PubMed  Google Scholar 

  8. Schuman EM, Madison DV. A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 1991, 254: 1503–1506.

    Article  CAS  PubMed  Google Scholar 

  9. Guix FX, Uribesalgo I, Coma M, Munoz FJ. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 2005, 76: 126–152.

    Article  CAS  PubMed  Google Scholar 

  10. McCann SM. The nitric oxide hypothesis of brain aging. Exp Gerontol 1997, 32: 431–440.

    Article  CAS  PubMed  Google Scholar 

  11. Rivier C. Role of gaseous neurotransmitters in the hypothalamic-pituitary-adrenal axis. Ann NY Acad Sci 2001, 933: 254–264.

    Article  CAS  PubMed  Google Scholar 

  12. Kalb RG, Agostini J. Molecular evidence for nitric oxide-mediated motor neuron development. Neuroscience 1993, 57: 1–8.

    Article  CAS  PubMed  Google Scholar 

  13. Li H, Gu X, Dawson VL, Dawson TM. Identification of calcium- and nitric oxide-regulated genes by differential analysis of library expression (DAzLE). Proc Natl Acad Sci U S A 2004, 101: 647–652.

    Article  CAS  PubMed  Google Scholar 

  14. Love S. Oxidative stress in brain ischemia. Brain Pathol 1999, 9: 119–131.

    Article  CAS  PubMed  Google Scholar 

  15. Luo CX, Zhu XJ, Zhou QG, Wang B, Wang W, Cai HH, et al. Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression. J Neurochem 2007, 103: 1872–1882.

    Article  CAS  PubMed  Google Scholar 

  16. Szabo C, Ischiropoulos H, Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 2007, 6: 662–680.

    Article  CAS  PubMed  Google Scholar 

  17. Andoh T, Lee SY, Chiueh CC. Preconditioning regulation of bcl-2 and p66shc by human NOS1 enhances tolerance to oxidative stress. FASEB J 2000, 14: 2144–2146.

    CAS  PubMed  Google Scholar 

  18. Jiang X, Mu D, Manabat C, Koshy AA, Christen S, Tauber MG, et al. Differential vulnerability of immature murine neurons to oxygen-glucose deprivation. Exp Neurol 2004, 190: 224–232.

    Article  CAS  PubMed  Google Scholar 

  19. Chen J, Tu Y, Moon C, Matarazzo V, Palmer AM, Ronnett GV. The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance. Dev Biol 2004, 269: 165–182.

    Article  CAS  PubMed  Google Scholar 

  20. Arbonés ML, Ribera J, Agullü L, Baltrons MA, Casanovas A, Riveros-Moreno V, et al. Characteristics of nitric oxide synthase type I of rat cerebellar astrocytes. Glia 1996, 18: 224–232.

    Article  PubMed  Google Scholar 

  21. Wang T, FitzGerald TJ, Haregewoin A. Differential expression of nitric oxide synthase in EGF-responsive mouse neural precursor cells. Cell Tissue Res 1999, 296: 489–497.

    Article  CAS  PubMed  Google Scholar 

  22. Torroglosa A, Murillo-Carretero M, Romero-Grimaldi C, Matarredona ER, Campos-Caro A, Estrada C. Nitric oxide decreases subventricular zone stem cell proliferation by inhibition of epidermal growth factor receptor and phosphoinostitide-3-kinase/Akt pathway. Stem Cells 2007, 25: 88–97.

    Article  CAS  PubMed  Google Scholar 

  23. Wang H, Kohr MJ, Traynham CJ, Wheeler DG, Janssen PM, Ziolo MT. Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban. Am J Physiol Cell Physiol 2008, 294: C1566–C1575.

    Article  CAS  PubMed  Google Scholar 

  24. Percival JM, Anderson KN, Huang P, Adams ME, Froehner SC. Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle. J Clin Invest 2010, 120: 816–826.

    Article  CAS  PubMed  Google Scholar 

  25. Pluta RM. Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl 2008, 104: 139–147.

    Article  CAS  PubMed  Google Scholar 

  26. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 1996, 84: 757–767.

    Article  CAS  PubMed  Google Scholar 

  27. Bender AT, Demady DR, Osawa Y. Ubiquitination of neuronal nitric-oxide synthase in vitro and in vivo. J Biol Chem 2000, 275: 17407–17411.

    Article  CAS  PubMed  Google Scholar 

  28. Corso-Díaz X, Krukoff TL. nNOSalpha and nNOSbeta localization to aggresome-like inclusions is dependent on HSP90 activity. J Neurochem 2010, 114: 864–887.

    Article  PubMed  CAS  Google Scholar 

  29. Eliasson MJ, Blackshaw S, Schell MJ, Snyder SH. Neuronal nitric oxide synthase alternatively spliced forms: prominent functional localizations in the brain. Proc Natl Acad Sci U S A 1997, 94: 3396–3401.

    Article  CAS  PubMed  Google Scholar 

  30. Silvagno F, Xia H, Bredt DS. Neuronal nitric-oxide synthasemu, an alternatively spliced isoform expressed in differentiated skeletal muscle. J Biol Chem 1996, 271: 11204–11208.

    Article  CAS  PubMed  Google Scholar 

  31. Kolesnikov YA, Chereshnev I, Criesta M, Pan YX, Pasternak GW. Opposing actions of neuronal nitric oxide synthase isoforms in formalin-induced pain in mice. Brain Res 2009, 1289: 14–21.

    Article  CAS  PubMed  Google Scholar 

  32. Kolesnikov YA, Pan YX, Babey AM, Jain S, Wilson R, Pasternak GW. Functionally differentiating two neuronal nitric oxide synthase isoforms through antisense mapping: evidence for opposing NO actions on morphine analgesia and tolerance. Proc Natl Acad Sci U S A 1997, 94: 8220–8225.

    Article  CAS  PubMed  Google Scholar 

  33. Sagami I, Daff S, Shimizu T. Intra-subunit and inter-subunit electron transfer in neuronal nitric-oxide synthase: effect of calmodulin on heterodimer catalysis. J Biol Chem 2001, 276: 30036–30042.

    Article  CAS  PubMed  Google Scholar 

  34. Noguchi T, Sagami I, Daff S, Shimizu T. Important role of tetrahydrobiopterin in no complex formation and interdomain electron transfer in neuronal nitric-oxide synthase. Biochem Biophys Res Commun 2001, 282: 1092–1097.

    Article  CAS  PubMed  Google Scholar 

  35. Hemmens B, Goessler W, Schmidt K, B Mayer B. Role of bound zinc in dimmer stabilization but not enzyme activity of neuronal nitric-oxide synthase. J Biol Chem 2000, 275: 35786–35791.

    Article  CAS  PubMed  Google Scholar 

  36. Bros M, Boissel JP, Godtel-Armbrust U, Forstermann U. The untranslated region of exon 2 of the human neuronal nitric oxide synthase (NOS1) gene exerts regulatory activity. Gene 2007, 405: 36–46.

    Article  CAS  PubMed  Google Scholar 

  37. Wei X, Sasaki M, Huang H, Dawson VL, Dawson TM. The orphan nuclear receptor, steroidogenic factor 1, regulates neuronal nitric oxide synthase gene expression in pituitary gonadotropes. Mol Endocrinol 2002, 16: 2828–2839.

    Article  CAS  PubMed  Google Scholar 

  38. Komar AA, Hatzoglou M. Internal ribosome entry sites in cellular mRNAs: mystery of their existence. J Biol Chem 2005, 280: 23425–23428.

    Article  CAS  PubMed  Google Scholar 

  39. Boissel JP, Bros M, Schröck A, Gödtel-Armbrust U, Förstermann U. Cyclic AMP-mediated upregulation of the expression of neuronal NO synthase in human A673 neuroepithelioma cells results in a decrease in the level of bioactive NO production: analysis of the signaling mechanisms that are involved. Biochemistry 2004, 43: 7197–7206.

    Article  CAS  PubMed  Google Scholar 

  40. Sasaki M, Gonzalez-Zulueta M, Huang H, Herring WJ, Ahn S, Ginty DD, et al. Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism. Proc Natl Acad Sci U S A 2000, 97: 8617–8622.

    Article  CAS  PubMed  Google Scholar 

  41. Wheeler DG, Barrett CF, Groth RD, Safa P, Tsien RW. CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling. J Cell Biol 2008, 183: 849–863.

    Article  CAS  PubMed  Google Scholar 

  42. Peunova N, Enikolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature 1993, 364: 450–453.

    Article  CAS  PubMed  Google Scholar 

  43. Billecke SS, Draganov DI, Morishima Y, Murphy PJ, Dunbar AY, Pratt WB, et al. The role of hsp90 in hemedependent activation of apo-neuronal nitric-oxide synthase. J Biol Chem 2004, 279: 30252–30258.

    Article  CAS  PubMed  Google Scholar 

  44. Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, et al. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A 2005, 102: 8525–8530.

    Article  CAS  PubMed  Google Scholar 

  45. Peng HM, Morishima Y, Clapp KM, Lau M, Pratt WB, Osawa Y. Dynamic cycling with Hsp90 stabilizes neuronal nitric oxide synthase through calmodulin-dependent inhibition of ubiquitination. Biochemistry 2009, 48: 8483–8490.

    Article  CAS  PubMed  Google Scholar 

  46. Song T, Hatano N, Horii M, Tokumitsu H, Yamaguchi F, Tokuda M, et al. Calcium/calmodulin-dependent protein kinase I inhibits neuronal nitric-oxide synthase activity through serine 741 phosphorylation. FEBS Lett 2004, 570: 133–137.

    Article  CAS  PubMed  Google Scholar 

  47. Li H, Poulos TL. Structure-function studies on nitric oxide synthases. J Inorg Biochem 2005, 99: 293–305.

    Article  CAS  PubMed  Google Scholar 

  48. Stuehr DJ, Santolini J, Wang ZQ, Wei CC, Adak S. Update on mechanism and catalytic regulation in the NO synthases. J Biol Chem 2004, 279: 36167–36170.

    Article  CAS  PubMed  Google Scholar 

  49. Haque MM, Panda K, Tejero J, Aulak KS, Fadlalla MA, Mustovich AT, et al. A connecting hinge represses the activity of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 2007, 104: 9254–9259.

    Article  CAS  PubMed  Google Scholar 

  50. Ilagan RP, Tiso M, Konas DW, Hemann C, Durra D, Hille R, et al. Differences in a conformational equilibrium distinguish catalysis by the endothelial and neuronal nitric-oxide synthase flavoproteins. J Biol Chem 2008, 283: 19603–19615.

    Article  CAS  PubMed  Google Scholar 

  51. Rameau GA, Chiu LY, Ziff EB. Bidirectional regulation of neuronal nitric oxide synthase phosphorylation at serine 847 by the N-methyl-D-aspartate receptor. J Biol Chem 2004, 279: 4307–4314.

    Article  CAS  Google Scholar 

  52. Jaffrey SR, Snyder SH. PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science 1996, 274: 774–777.

    Article  CAS  PubMed  Google Scholar 

  53. Fan JS, Zhang Q, Li M, Tochio H, Yamazaki T, Shimizu M, et al. Protein inhibitor of neuronal nitric-oxide synthase, PIN, binds to a 17-amino acid residue fragment of the enzyme. J Biol Chem 1998, 273: 33472–33481.

    Article  CAS  PubMed  Google Scholar 

  54. Nourry C, Grant SGN, Borg JP. PDZ domain proteins: plug and play! Sci STKE 2003, 2003: RE7.

    Article  PubMed  Google Scholar 

  55. Lemaire JF, McPherson PS. Binding of Vac14 to neuronal nitric oxide synthase: characterisation of a new internal PDZ-recognition motif. FEBS Lett 2006, 580: 6948–6954.

    Article  CAS  PubMed  Google Scholar 

  56. Cui H, Hayashi A, Sun HS, Belmares MP, Cobey C, Phan Schweizer TJ, et al. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 2007, 27: 9901–9915.

    Article  CAS  PubMed  Google Scholar 

  57. Chen M, Cheng C, Yan M, Niu S, Gao S, Shi S, et al. Involvement of CAPON and nitric oxide synthases in rat muscle regeneration after peripheral nerve injury. J Mol Neurosci 2008, 34: 89–100.

    Article  CAS  PubMed  Google Scholar 

  58. Sattler R, Xiong Z, Lu WY, Hafner M, MacDonald JF, Tymianski M. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 1999, 284: 1845–1848.

    Article  CAS  PubMed  Google Scholar 

  59. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999, 51: 7–61.

    CAS  PubMed  Google Scholar 

  60. Hu M, Sun YJ, Zhou QG, Chen L, Hu Y, Luo CX, et al. Negative regulation of neurogenesis and spatial memory by NR2B-containing NMDA receptors. J Neurochem 2008, 106: 1900–1913.

    Article  CAS  PubMed  Google Scholar 

  61. Eugenin EA, King JE, Nath A, Calderon TM, Zukin RS, Bennett MV, et al. HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci U S A 2007, 104: 3438–3443.

    Article  CAS  PubMed  Google Scholar 

  62. Aarts MM, Tymianski M. Novel treatment of excitotoxicity: targeted disruption of intracellular signaling from glutamate receptors. Biochem Pharmacol 2003, 66: 877–886.

    Article  CAS  PubMed  Google Scholar 

  63. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2002, 298: 846–850.

    Article  CAS  PubMed  Google Scholar 

  64. Cao J, Vijolainen JI, Dart C, Warwick HK, Leyland ML, Courtney MJ. The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J Cell Biol 2005, 168: 117–126.

    Article  CAS  PubMed  Google Scholar 

  65. Jaffrey SR, Snowman AM, Eliasson MJ, Cohen NA, Snyder SH. CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 1998, 20: 115–124.

    Article  CAS  PubMed  Google Scholar 

  66. Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH. Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 2000, 28: 183–193.

    Article  CAS  PubMed  Google Scholar 

  67. Cheah JH, Kim SF, Hester LD, Clancy KW, Patterson 3rd SE, Papadopoulos V, et al. NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 2006, 51: 431–440.

    Article  CAS  PubMed  Google Scholar 

  68. Gao H, Gao Y, Li X, Shen A, Yan M. Spatiotemporal patterns of dexamethasone-induced Ras protein 1 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis. J Mol Neurosci 2010, 41: 198–209.

    Article  CAS  PubMed  Google Scholar 

  69. Richier L, Williton K, Clattenburg L, Colwill K, O’Brien M, Tsang C, et al. NOS1AP associates with Scribble and regulates dendritic spine development. J Neurosci 2010, 30: 4796–4805.

    Article  CAS  PubMed  Google Scholar 

  70. Firestein BL, Bredt DS. Interaction of neuronal nitric-oxide synthase and phosphofructokinase-M. J Biol Chem 1999, 274: 10545–10550.

    Article  CAS  PubMed  Google Scholar 

  71. Funke L, Dakoji S, Bredt DS. Membrane-associated guanylate kinases regulate adhesion and plasticity at cell junctions. Annu Rev Biochem 2005, 74: 219–245.

    Article  CAS  PubMed  Google Scholar 

  72. Chen X, Vinade L, Leapman RD, Petersen JD, Nakagawa T, Phillips TM, et al. Mass of the postsynaptic density and enumeration of three key molecules. Proc Natl Acad Sci U S A 2005, 102: 11551–11556.

    Article  CAS  PubMed  Google Scholar 

  73. Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 1998, 396: 433–439.

    Article  CAS  PubMed  Google Scholar 

  74. Stein, V, House DR, Bredt DS, Nicoll RA. Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression. J Neurosci 2003, 23: 5503–5506.

    CAS  PubMed  Google Scholar 

  75. Schnell, E, Sizemore M, Karimzadegan S, Chen L, Bredt DS, Nicoll RA. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc Natl Acad Sci U S A 2002, 99: 13902–13907.

    Article  CAS  PubMed  Google Scholar 

  76. Ehrlich I, Malinow R. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci 2004, 24: 916–927.

    Article  CAS  PubMed  Google Scholar 

  77. Nikonenko I, Boda B, Steen S, Knott G, Welker E, Muller D. PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling. J Cell Biol 2008, 183: 1115–1127.

    Article  CAS  PubMed  Google Scholar 

  78. Nott A, Watson PM, Robinson JD, Crepaldi L, Riccio A. Snitrosylation of histone deacetylase 2 induces chromation remodeling in neurons. Nature 2008; 455: 411–415.

    Article  CAS  PubMed  Google Scholar 

  79. Palop JJ, Chin J, Mucke L. A network dysfunction perspective on neurodegenerative diseases. Nature 2006, 443: 768–773.

    Article  CAS  PubMed  Google Scholar 

  80. Small DH. Network dysfunction in Alzheimer’s disease: does synaptic scaling drive disease progression? Trends Mol Med 2008, 14: 103–108.

    CAS  PubMed  Google Scholar 

  81. Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol 2003, 2: 229–237.

    Article  CAS  PubMed  Google Scholar 

  82. Cepeda C, Wu N, André VM, Cummings DM, Levine MS. The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 2007, 81: 253–271.

    Article  CAS  PubMed  Google Scholar 

  83. Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 2009, 29: 3442–3452.

    Article  CAS  PubMed  Google Scholar 

  84. Kim HJ, Martemyanov KA, Thayer SA. Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. J Neurosci 2008, 28: 12604–12613.

    Article  CAS  PubMed  Google Scholar 

  85. Sunico CR, Portillo F, González-Forero D, Moreno-López B. Nitric oxide-directed synaptic remodeling in the adult mammal CNS. J Neurosci 2005, 25: 1448–1458.

    Article  CAS  PubMed  Google Scholar 

  86. Anneser JM, Cookson MR, Ince PG, Shaw PJ, Borasio GD. Glial cells of the spinal cord and subcortical white matter upregulate neuronal nitric oxide synthase in sporadic amyotrophic lateral sclerosis. Exp Neurol 2001, 171: 418–421.

    Article  CAS  PubMed  Google Scholar 

  87. Catania MV, Aronica E, Yankaya B, Troost D. Increased expression of neuronal nitric oxide synthase spliced variants in reactive astrocytes of amyotrophic lateral sclerosis human spinal cord. J Neurosci 2001, 21(RC148): 1–5.

    Google Scholar 

  88. Sasaki S, Shibata N, Iwata M. Neuronal nitric oxide synthase immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol 2001, 101: 351–357.

    CAS  PubMed  Google Scholar 

  89. Eve DJ, Nisbet AP, Kingsbury AE, Hewson EL, Daniel SE, Lees AJ, et al. Basal ganglia neuronal nitric oxide synthase mRNA expression in Parkinson’s disease. Brain Res Mol Brain Res 1998, 63: 62–71.

    Article  CAS  PubMed  Google Scholar 

  90. Lüth HJ, Holzer M, Gertz HJ, Arendt T. Aberrant expression of nNOS in pyramidal neurons in Alzheimer’s disease is highly colocalized with p21ras and p16INK4a. Brain Res 2000, 852: 45–55.

    Article  PubMed  Google Scholar 

  91. Simic G, Lucassen PJ, Krsnik Z, Kruslin B, Kostovic I, Winblad B, et al. nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer’s disease. Exp Neurol 2000, 165: 12–26.

    Article  CAS  PubMed  Google Scholar 

  92. Fernández-Vizarra P, Fernández AP, Castro-Blanco S, Encinas JM, Serrano J, Bentura ML, et al. Expression of nitric oxide system in clinically evaluated cases of Alzheimer’s disease. Neurobiol Dis 2004, 15: 287–305.

    Article  PubMed  CAS  Google Scholar 

  93. Deckel AW, Tang V, Nuttal D, Gary K, Elder R. Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice. Brain Res 2002, 939: 76–86.

    Article  CAS  PubMed  Google Scholar 

  94. Pérez-Severiano F, Escalante B, Vergara P, Ríos C, Segovia J. Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington’s disease mutation. Brain Res 2002, 951: 36–42.

    Article  PubMed  Google Scholar 

  95. Wu HH, Williams CV, McLoon SC. Involvement of nitric oxide in the elimination of a transient retinotectal projection in development. Science 1994, 265: 1593–1596.

    Article  CAS  PubMed  Google Scholar 

  96. Moreno-López B, González-Forero D. Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects. Rev Neurosci 2006, 17: 309–357.

    PubMed  Google Scholar 

  97. Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, et al. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 2009, 324: 102–105.

    Article  CAS  PubMed  Google Scholar 

  98. Sunico CR, González-Forero D, Domínguez G, García-Verdugo JM, Moreno-López B. Nitric oxide induces pathological synapse loss by a protein kinase G-, Rho kinase-dependent mechanism preceded by myosin light chain phosphorylation. J Neurosci 2010, 30: 973–984.

    Article  CAS  PubMed  Google Scholar 

  99. Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature 2000, 407: 963–970.

    Article  CAS  PubMed  Google Scholar 

  100. Gage FH. Mammalian neural stem cells. Science 2000, 287: 1433–1438.

    Article  CAS  PubMed  Google Scholar 

  101. Temple S. The development of neural stem cells. Nature 2001, 414: 112–117.

    Article  CAS  PubMed  Google Scholar 

  102. Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature 2002, 417: 39–44.

    Article  CAS  PubMed  Google Scholar 

  103. Macklis JD. Neurobiology: New memories from new neurons. Nature 2001, 410: 314–317.

    Article  CAS  PubMed  Google Scholar 

  104. Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H, et al. Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci U S A 2003, 100: 9566–9571.

    Article  CAS  PubMed  Google Scholar 

  105. Moreno-López B, Romero-Grimaldi C, Noval JA, Murillo-Carretero M, Matarredona ER, Estrada C. Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci 2004, 24: 85–95.

    Article  PubMed  CAS  Google Scholar 

  106. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, et al. Neurogenesis in the adult human hippocampus. Nature Med 1998, 4: 1313–1317.

    Article  CAS  PubMed  Google Scholar 

  107. van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999, 2: 266–270.

    Article  PubMed  Google Scholar 

  108. Parent JM, Valentin VV, Lowenstein DH. Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. J Neurosci 2002, 22: 3174–3188.

    CAS  PubMed  Google Scholar 

  109. Liu J, Solway K, Messing RO, Sharp FR. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 1998, 18: 7768–7778.

    CAS  PubMed  Google Scholar 

  110. Zhu DY, Lu SH, Sun HS, Lu YM. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 2003, 23: 223–229.

    CAS  PubMed  Google Scholar 

  111. Zhu DY, Wei JS, Lau L, Liu SH, Lu YM. Activation of cAMP response element binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 2004, 101: 9453–9457.

    Article  CAS  PubMed  Google Scholar 

  112. Kokaia Z, Lindvall O. Neurogenesis after ischaemic brain insults. Curr Opin Neurobiol 2003, 13: 127–132.

    Article  CAS  PubMed  Google Scholar 

  113. Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000, 405: 951–955.

    Article  CAS  PubMed  Google Scholar 

  114. Chen J, Magavi SS, Macklis JD. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc Natl Acad Sci U S A 2004, 101: 16357–16362.

    Article  CAS  PubMed  Google Scholar 

  115. Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002, 110: 429–441.

    Article  CAS  PubMed  Google Scholar 

  116. Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002, 8: 963–970.

    Article  CAS  PubMed  Google Scholar 

  117. Matarredona ER, Murillo-Carretero M, Moreno-López B, Estrada C. Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone. Brain Res 2004, 995: 274–284.

    Article  CAS  PubMed  Google Scholar 

  118. Zhu XJ, Hua Y, Jiang J, Zhou QG, Luo CX, Han X, et al. Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation. Neuroscience 2006, 141: 827–836.

    Article  CAS  PubMed  Google Scholar 

  119. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 2001, 98: 4710–4715.

    Article  CAS  PubMed  Google Scholar 

  120. Zhou QG, Hu Y, Hua Y, Hu M, Luo CX, Han X, et al. Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis. J Neurochem 2007, 103: 1843–1854.

    Article  CAS  PubMed  Google Scholar 

  121. Zhang R, Zhang L, Zhang Z, Wang Y, Lu M, Lapointe M, et al. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 2001, 50: 602–611.

    Article  CAS  PubMed  Google Scholar 

  122. Hua Y, Huang XY, Zhou L, Zhou QG, Hu Y, Luo CX, et al. DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis. Psychopharmacology 2008, 200: 231–242.

    Article  CAS  PubMed  Google Scholar 

  123. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: Diversity, development and disease. Curr Opin Neurobiol 2001, 11: 327–335.

    Article  CAS  PubMed  Google Scholar 

  124. Prybylowski K, Wenthold RJ. N-Methyl-D-aspartate receptors: Subunit assembly and trafficking to the synapse. J Biol Chem 2004, 279: 9673–9676.

    Article  CAS  PubMed  Google Scholar 

  125. Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 2000, 3: 661–669.

    Article  CAS  PubMed  Google Scholar 

  126. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM. Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 1996, 16: 2479–2487.

    CAS  PubMed  Google Scholar 

  127. Hecker M, Mülsch A, Busse R. Subcellular localization and characterization of neuronal nitric oxide synthase. J Neurochem 1994, 62: 1524–1529.

    Article  CAS  PubMed  Google Scholar 

  128. Rothe F, Canzler U, Wolf G. Subcellular localization of the neuronal isoform of nitric oxide synthase in the rat brain: a critical evaluation. Neuroscience 1998, 83: 259–269.

    Article  CAS  PubMed  Google Scholar 

  129. Takagi N, Logan R, Teves L, Wallace MC, Gurd JW. Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia. J Neurochem 2000, 74: 169–178.

    Article  CAS  PubMed  Google Scholar 

  130. Zhou L, Li F, Xu HB, Luo CX, Wu HY, Zhu MM, et al. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med 2010, 16: 1439–1443.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pharmacology, School of Pharmacy, Laboratory of Cerebrovascular Disease, Nanjing Medical University, Nanjing, 210029, China

    Chun-Xia Luo  (罗春霞) & Dong-Ya Zhu  (朱东亚)

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Correspondence to Dong-Ya Zhu  (朱东亚).

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Luo, CX., Zhu, DY. Research progress on neurobiology of neuronal nitric oxide synthase. Neurosci. Bull. 27, 23–35 (2011). https://doi.org/10.1007/s12264-011-1038-0

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