NMDA receptor regulation of nNOS phosphorylation and induction of neuron death

Rameau, Gerald A.; Chiu, Ling-Yu; Ziff, Edward B.

doi:10.1016/j.neurobiolaging.2003.07.002

Cited by 53 publications

(47 citation statements)

References 47 publications

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“…4A, lanes 3 and 4). These results are consistent with our previous studies of a decrease in the overall level of nNOS phosphorylation after a pathological stimulation by glutamate involves PP1 (30). Quantification of the data revealed that glutamate treatment at 100 M for 60 min reduced the phosphorylation of nNOS at Ser 847 up to 50% of its constitutive level (values represent means Ϯ S.E., n ϭ 4, p Ͻ 0.001) (Fig.…”

Section: Localization Of Ser 847 -Po 4 Nnos At Synapses In Hippocampasupporting

confidence: 92%

“…We have shown previously that NMDAR activation by excitotoxic concentrations of agonist induces an overall dephosphorylation of nNOS (30). Here, we extend these results by demonstrating that stimulation of culture primary cortical neurons with a physiologic level of glutamate results in an NMDAR-mediated increase in phosphorylation at Ser 847 of nNOS.…”

Section: Discussionsupporting

confidence: 79%

“…The magnitude of the increase of Ca 2ϩ correlated with the increase in the concentration of glutamate (56). We have demonstrated previously that NMDAR regulation of the overall phosphorylation of nNOS is independent of AMPA receptors or L-type voltage-sensitive calcium channels (30). In the current studies, we have demonstrated an NMDAR-dependent increase of phosphorylation at Ser 847 in cortical cultured neurons treated with 5 M glutamate.…”

Section: Discussionsupporting

confidence: 65%

“…Because Ca 2ϩ -dependent activation of nNOS by the NMDAR has been linked to NMDAR excitotoxic effects (6, 7, 20, 26 -30), we have also analyzed the NMDAR-mediated mechanism of modulation of phosphorylation of nNOS. We have shown that after excitotoxic activation of the NMDAR in cultured primary cortical neurons, nNOS undergoes an overall dephosphorylation by a pathway dependent on the phosphatases calcineurin and PP1/PP2A (30).…”

Section: Nnosmentioning

confidence: 99%

“…We demonstrated previously that NT, detected by an anti-NT antibody, can be used as a measure of NO accumulation after the activation of nNOS by the NMDAR (30). The levels of Ser 847 -PO 4 nNOS and NT were measured in individual cells by quantitative fluorometry, as described previously (30).…”

Section: Cellular Analysis Of Nos Activity and Levels Of Ser 847 -Po mentioning

confidence: 99%

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Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-d-aspartate Receptor

Rameau¹,

Chiu

Ziff

2004

Journal of Biological Chemistry

120

104

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847 by different doses of glutamate suggests two mechanisms with opposite effects: 1) a time-dependent negative feedback induced by physiological concentrations of glutamate that limits nNOS activation and precludes the overproduction of NO; and 2) a pathological stimulation by high concentrations of glutamate that leads to unregulated nNOS activation and production of toxic levels of NO. These mechanisms may share pathways, respectively, with NMDA receptor-induced forms of synaptic plasticity and excitotoxicity. nNOS 1 is an enzyme expressed in brain which catalyzes the conversion of arginine to citrulline and NO (1-4), the latter a novel diffusible second messenger with multiple physiologic and pathologic effects (3, 5-7). One regulator of nNOS is the NMDAR, a tetrameric cation channel consisting of NR1 and NR2 subunits which is targeted to excitatory synapses where it functions in neural plasticity (8). Stimulation of the NMDAR by glutamate and glycine induces the influx of Ca 2ϩ through the receptor pore, thereby activating Ca 2ϩ -dependent NMDAR functions (9 -12). PSD95, a scaffolding protein, binds both the NMDAR and nNOS at excitatory synapses and assembles them into a macromolecular signaling complex in which nNOS is under NMDAR control (13-19). Suppression of PSD95 expression blocks NMDAR and Ca 2ϩ -dependent nNOS activation, and uncoupling of the NMDAR from PSD95 suppresses NMDAR signaling (14,20).Transient elevations in intracellular [Ca 2ϩ ] following NMDAR activation stimulate nNOS by promoting the binding of Ca 2ϩ -calmodulin (Ca 2ϩ -CaM). In addition, it has been shown that the activity of nNOS undergoes complex regulation by phosphorylation (21-23). Of particular note, the protein kinase CaMKII phosphorylates recombinant nNOS at Ser 847 , which reduces nNOS activity by inhibiting the binding of Ca 2ϩ -CaM (23, 24). However, the NMDAR-induced mechanism of regulation of nNOS by phosphorylation at specific residues remains largely unknown.We have shown previously that mutations at the apex of the pore of the NMDAR NR1 subunit which block Ca 2ϩ entry through the channel reduce NMDAR-dependent excitotoxicity in heterologous cells and neurons (25). Because Ca 2ϩ -dependent activation of nNOS by the NMDAR has been linked to NMDAR excitotoxic effects (6, 7, 20, 26 -30), we have also analyzed the NMDAR-mediated mechanism of modulation of phosphorylation of nNOS. We have shown that after excitotoxic activation of the NMDAR in cultured primary cortical neurons, nNOS undergoes an overall dephosphorylation by a pathway dependent on the phosphatases calcineurin and PP1/PP2A (30).It is well established that the effectiveness of synapses and even the viability of the neuron can be altered by NMDAR-dependent activity that can be achieved by various patterns of stimulation. Here, we analyze the effects of NMDAR activation on the level of phosphorylation of nNOS at Ser 847 , a modification implicated in the regulation of nNOS. We show that the NMDAR induces a novel bidirectional control of phosphorylation of nNOS...

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Section: Localization Of Ser 847 -Po 4 Nnos At Synapses In Hippocampasupporting

confidence: 92%

Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 65%

Section: Nnosmentioning

confidence: 99%

Section: Cellular Analysis Of Nos Activity and Levels Of Ser 847 -Po mentioning

confidence: 99%

See 3 more Smart Citations

Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-d-aspartate Receptor

Rameau¹,

Chiu

Ziff

2004

Journal of Biological Chemistry

120

104

View full text Add to dashboard Cite

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Stimulation of NMDA and AMPA glutamate receptors elicits distinct concentration dynamics of nitric oxide in rat hippocampal slices

2008

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Nitric oxide ((*)NO) is an intercellular messenger implicated in memory formation and neurodegeneration in the hippocampus. Owing to its physical and chemical properties, the concentration dynamics of (*)NO is a critical issue in determining its bioactivity as a signaling molecule. Its production is closely related to glutamate N-methyl-D-aspartate (NMDA) receptors, following a rise in intracellular calcium levels. However, that dependent on alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors remains elusive and controversial, despite reports describing a role for these receptors in other brain regions, largely because of lack of quantitative and dynamic measurements of (*)NO. Using a (*)NO-selective microsensor inserted in the diffusional spread of (*)NO in the CA1 region of rat hippocampal slices, we measured its real-time endogenous production, following activation of ionotropic glutamate receptors and under tissue physiological oxygen tension. Both NMDA and AMPA stimulation resulted in a concentration-dependent (*)NO production but encompassing distinct kinetics for lag phases and slower rates of (*)NO production were observed for AMPA stimulation. Robustness of the results was achieved instrumentally and pharmacologically, by means of nitric oxide synthase (NOS) inhibitors and antagonists of NMDA (D-(-)-2-amino-5-phosphonopentanoic acid, AP5) and AMPA (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NBQX) receptors. When using glutamate as a stimulus, (*)NO production was of lower magnitude in the presence of AP5 plus NBQX than with AP5 alone, suggesting that even when NMDA receptors are inhibited Ca(2+) rises to levels to induce a peak of (*)NO from the background. Whereas extracellular Ca(2+) was required for the (*)NO signals, Philanthotoxin-4,3,3 (PhTX-4,3,3) a toxin used to target Ca(2+)-permeable AMPA receptors, attenuated (*)NO production. These observations are interpreted on basis of a distinct coupling between the glutamate receptors and neuronal NOS. A role for Ca(2+)-permeable AMPA receptors in the Ca(2+) activation of neuronal NOS is suggested.

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Phenotype, Compartmental Organization and Differential Vulnerability of Nigral Dopaminergic Neurons

González‐Hernández

Afonso-Oramas

Cruz-Muros

2009

Birth, Life and Death of Dopaminergic Neurons in the Substantia Nigra

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NMDA receptor regulation of nNOS phosphorylation and induction of neuron death

Cited by 53 publications

References 47 publications

Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-d-aspartate Receptor

Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-d-aspartate Receptor

Stimulation of NMDA and AMPA glutamate receptors elicits distinct concentration dynamics of nitric oxide in rat hippocampal slices

Phenotype, Compartmental Organization and Differential Vulnerability of Nigral Dopaminergic Neurons

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