Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications

Zhou, Li; Zhu, Dong‐Ya

doi:10.1016/j.niox.2009.03.001

Cited by 571 publications

(466 citation statements)

References 123 publications

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“…Therefore, NADPH-d staining pattern and its relation to NOS were required interpretation with caution and only following profound immunobiological and/or biochemical control experiments (Ott and Elphick, 2002). It also concerns the immuno-electron microscopic visualization of NOS since ultrastructural and biochemical studies suggested that a significant amount and activity of NOS are of cytosolic location (Hecker et al, 1994;Huang et al, 1997;Zhou and Zhu, 2009). Hence the exact identity of the ultrastructural NADPH-d reaction product, which is only membrane-bound, remains for further discussion (Rothe et al, 1998).…”

Section: In Invertebratesmentioning

confidence: 99%

“…In the nervous system NO is synthetized by the neuronal form of nitric oxide synthase (nNOS), and exerts its effect mainly by inducing cyclic guanosine monophosphate (cGMP) synthesis through the activation of its receptor, soluble guanylate cyclase (sGC), or influences protein activity via S-nitrosylation of defined cysteine residues. In the past twenty years the involvement of NO in different processes of the mammalian nervous system, such as regulation of haemodynamics in the CNS, neuronal development, memory formation and consolidation, neuroprotection as well as neurodegeneration, has been well documented (Zhou and Zhu, 2009;Vincent, 2010). NO is considered to be a transmitter or modulator acting alone or as a co-transmitter in anterograde way in the cerebral cortex, cerebellum, brainstem, and the peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

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Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

Nacsa

Elekes

Serfözö

2015

Micron

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This manuscript is contextually identical with the following published paper:For the first time, we have shown that NADPH-diaphorase reactivity and NOS immunoreactivity are bound to transmitter vesicle membranes in varicosities of ganglionic neuropil of an invertebrate. The presence of NOS in certain synaptic configurations of the snail CNS suggests a role of NO in fast and target specific interneuronal signaling processes. 3 ABSTRACTComparative studies on the nervous system revealed that nitric oxide (NO) retains its function through the evolution. In vertebrates NO can act in different ways: it is released solely or as a co-transmitter, released from presynaptic or postsynaptic site, spreads as a volumetric signal or targets synaptic proteins. In invertebrates, however, the possible sites of NO release have not yet been identified. Therefore, in the present study, the subcellular distribution of the NO synthase (NOS) was examined in the central nervous system (CNS) of two gastropod species, the terrestrial snail, Helix pomatia and the pond snail, Lymnaea stagnalis, which are model species in comparative neurobiology. For the visualization of NOS NADPH-diaphorase histochemistry and an immunohistochemical procedure using a universal anti-NOS antibody were applied. At light microscopic level both techniques labeled identical structures in sensory tracts ramifying in the neuropils of central ganglia and cell bodies of the Lymnaea and Helix CNS. At ultrastructural level NADPH-d reactive/NOS-immunoreactive materials were localized on the nuclear envelope and membrane segments of the rough and smooth endoplasmic reticulum, as well as the cell membrane and axolemma of positive perikarya. NADPH-d reactive and NOS-immunoreactive varicosities connected to neighboring neurons with both unspecialized and specialized synaptic contacts. In the varicosities, the majority of the NADPH-d reactive/NOS-immunoreactive membrane segments were detected in round and pleomorph agranular vesicles of small size (50-200 nm). However, only a small portion (16%) of the vesicles displayed the NADPH-d reactivity/NOSimmunoreactivity. No evidence for the postsynaptic location of NOS was found. Our results suggest that the localization of NADPH-diaphorase and NOS is identical in the snail nervous system. In contrast to vertebrates, however, NO seems to act exclusively in an anterograde way possibly released from membrane segments of the presynaptic transmitter vesicle surface. Based on the subcellular distribution of NOS, NO could be both a volume and a synaptic mediator, in addition NO may function as a co-transmitter.

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Section: In Invertebratesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

Nacsa

Elekes

Serfözö

2015

Micron

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“…In addition to NMDARs themselves, downstream molecules of NMDARs are also targets of drug design, and inhibiting nNOS showed protective effects in Alzheimer's disease model mice (Misra, Kuhad & Chopra, 2013; Yu et al., 2013). However, nNOS and the NO produced by nNOS play important roles in the normal function of neurons (Zhou & Zhu, 2009). Nonetheless, no nNOS inhibitor has yet to be approved for entry into clinical trials.…”

Section: Discussionmentioning

confidence: 99%

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

et al. 2018

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SummaryIn neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

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“…The haem domain is required for nNOS dimerization, a process necessary to convert inactive nNOS monomer into active dimers (Roman and Masters, 2006). The haem domain is also the final electron acceptor in the electron flow, which is required for NO production (Zhou and Zhu, 2009). The interaction between SU4312 and the haem domain of nNOS may disrupt nNOS dimerization and/or impair the electron transfer process, and consequently induce a non-competitive inhibition event.…”

Section: Discussionmentioning

confidence: 99%

The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

Cui

Zhang

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSESU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP + )-induced neurotoxicity and further explored the underlying mechanisms. EXPERIMENTAL APPROACHMPP + -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. KEY RESULTSSU4312 unexpectedly prevented MPP + -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 mM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. CONCLUSIONS AND IMPLICATIONSU4312 exhibited neuroprotection against MPP + at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity. Abbreviations

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Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications

Cited by 571 publications

References 123 publications

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

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Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications

Cited by 571 publications

References 123 publications

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

The anti‐cancer agent SU4312 unexpectedly protects against MPP+‐induced neurotoxicity via selective and direct inhibition of neuronal NOS

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The anti‐cancer agent SU4312 unexpectedly protects against MPP⁺‐induced neurotoxicity via selective and direct inhibition of neuronal NOS