Research progress on neurobiology of neuronal nitric oxide synthase

Luo, Chunxia; Zhu, Dong‐Ya

doi:10.1007/s12264-011-1038-0

Cited by 55 publications

(43 citation statements)

References 131 publications

(169 reference statements)

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“…At the postsynaptic density of glutamatergic synapses, nNOS, the NR2 subunit of the NMDAR, and CaM form part of the same macromolecular complex via the scaffold protein PSD-95 (postsynaptic density protein of 95 kD); this promotes the rapid Ca/CaM interactions with nNOS. 13 Neuronal NOS also interacts with heat shock protein (Hsp) 90, Hsp70, and with the protein inhibitor of nNOS, which regulate NOS activity. Several chemical signals in blood vessels activate eNOS.…”

Section: Regulation Of Expression and Activation Of Nosmentioning

confidence: 99%

“…For example, the alternative splicing of nNOS mRNA generates 5 subtypes of nNOS (nNOS-␣, nNOS-␤, nNOS-␥, nNOS-micro, and nNOS-2). 13 The 3 NOS isoforms differ in their mechanisms of activation, regulation, and catalytic activity (table 1). Neuronal NOS and eNOS are constitutively expressed and require calcium (Ca 2ϩ )/calmodulin (CaM) complexes for their activation.…”

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confidence: 99%

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Nitric oxide

Benarroch

2011

Neurology

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Nitric oxide (NO) is a gaseous chemical transmitter that is produced from the amino acid L-arginine by the members of the NO synthase (NOS) family of proteins. NO is involved in several important functions in the CNS and peripheral nervous system (PNS), including modulation of neurotransmission and regulation of local blood flow and immune responses. NO interacts with intracellular targets to trigger several signal transduction pathways. In the CNS, NO participates in synaptic modulation and plasticity, control of sleep, body temperature, and neurosecretion. In the PNS, NO mediates vasodilation and relaxation of the visceral smooth muscle. However, when produced in excess and in the setting of oxidative stress, NO becomes toxic, leading to formation of reactive nitrogen species (RNS), which cause cellular damage. These neurotoxic effects of NO derivatives may be involved in the pathogenesis of cerebral ischemia, inflammation, neoplasia, and neurodegenerative disorders. There are several comprehensive reviews on the physiologic and pathophysiologic roles of NO in the nervous system. 1-12 NITRIC OXIDE SYNTHASES Catalytic activity.The NOS family of enzymes catalyzes the oxidation of L-arginine to form L-citrulline and NO (figure 1). NOS is a dimeric enzyme; each monomer is composed of 2 distinct catalytic domains, an amino (NH2)-terminal oxygenase domain and a carboxy (COOH)-terminal reductase domain. The oxygenase domain is the binding site for heme, oxygen (O 2 ), tetrahydrobiopterin (BH4), and L-arginine; the reductase domain binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and reduced nicotinamide-adenine dinucleotide phosphate (NADPH). The catalytic mechanism involves flavin-mediated electron transport from NADPH to the heme center, where O 2 is reduced and incorporated into the guanidine nitrogen of L-arginine, producing NO and L-citrulline.

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Section: Regulation Of Expression and Activation Of Nosmentioning

confidence: 99%

mentioning

confidence: 99%

Nitric oxide

Benarroch

2011

Neurology

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“…Synaptic NMDARs are neuroprotective, and their activity triggers different neuroprotective signaling pathways, such as activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, activation of nuclear CREB (cAMP response element-binding protein), and enhancement of the antioxidant defense system (Hardingham, 2009). Extrasynaptic NMDARs preferentially initiate lethal downstream reactions including mitochondrial dysfunction (Murphy and Fiskum, 1999;Wang et al, 1999), oxidative stress (Kinouchi et al, 1991), and nitrosative stress (Aarts et al, 2003;Uehara et al, 2006;Luo and Zhu, 2011). Despite the increase in our understanding of NMDAR functions and their downstream signaling pathways, the molecular mechanisms underlying the coupling of NMDARs with different downstream signaling pathways are still far from well understood.…”

Section: Introductionmentioning

confidence: 99%

Adaptor Protein APPL1 Couples Synaptic NMDA Receptor with Neuronal Prosurvival Phosphatidylinositol 3-Kinase/Akt Pathway

Wang

et al. 2012

J. Neurosci.

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It is well known that NMDA receptors (NMDARs) can both induce neurotoxicity and promote neuronal survival under different circumstances. Recent studies show that such paradoxical responses are related to the receptor location: the former to the extrasynaptic and the latter to the synaptic. The phosphoinositide 3-kinase (PI3K)/Akt kinase cascade is a key pathway responsible for the synaptic NMDARdependent neuroprotection. However, it is still unknown how synaptic NMDARs are coupled with the PI3K/Akt pathway. Here, we explored the role of an adaptor protein-adaptor protein containing pH domain, PTB domain, and leucine zipper motif (APPL1)-in this signal coupling using rat cortical neurons. We found that APPL1 existed in postsynaptic densities and associated with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif. NMDARs, APPL1, and the PI3K/Akt cascade formed a complex in rat cortical neurons. Synaptic NMDAR activity increased the association of this complex, induced activation of the PI3K/Akt pathway, and consequently protected neurons against starvation-induced apoptosis. Perturbing APPL1 interaction with PSD95 by a peptide comprising the APPL1 C-terminal PDZ-binding motif dissociated the PI3K/Akt pathway from NMDARs. Either the peptide or lentiviral knockdown of APPL1 blocked synaptic NMDAR-dependent recruitment and activation of PI3K/Akt pathway, and consequently blocked synaptic NMDAR-dependent neuroprotection. These results suggest that APPL1 contributes to connecting synaptic NMDARs with the intracellular PI3K/Akt cascade and the downstream prosurvival signaling pathway in rat cortical neurons.

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“…JANEX-1 [20], antiinflammatory cytokines [21], prostacyclin [22] or some plant extracts [23] prevents cytokine-induced iNOS expression and cytokine toxicity in insulin-secreting cells [1,24,25]. The expression of nNOS is controlled by alternative splicing and the transcription factor CREB [26] and its activity can be regulated by Hsp90, calmodulin and other factors [1,26,27]. 5.…”

Section: Discussionmentioning

confidence: 99%