Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex

Lei, Sizheng Z.; Pan, Zhuo Hua; Aggarwal, Sanjay K.; Chen, Huei Sheng Vincent; Hartman, Jonathan; Sucher, Nikolaus J.; Lipton, Stuart A.

doi:10.1016/0896-6273(92)90130-6

Cited by 720 publications

(414 citation statements)

References 47 publications

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“…10 Electrophysiological studies have demonstrated this inhibitory effect of NO on the NMDA receptor-associated channel. 6,8,44 Moreover, as mentioned earlier, as the oxygen tension is lowered (a pO 2 of 10-20 torr is found in normal brain, and even lower levels under hypoxic/ischemic conditions), the NMDA receptor becomes more sensitive to inhibition by S-nitrosylation. 65 Unfortunately, nitroglycerin itself is not very attractive as a neuroprotective agent.…”

Section: Future Therapeutics: Nitromemantinesmentioning

confidence: 76%

“…30,[41][42][43] In general, NO exerts physiological and some pathophysiological effects via stimulation of guanylate cyclase to form cyclic guanosine-3 0 , 5 0 -monophosphate (cGMP) or through S-nitros(yl)ation of regulatory protein thiol groups. 5,6,44,45 S-nitrosylation is the covalent addition of an NO group to a critical cysteine thiol/ sulfhydryl (RSH or, more properly, thiolate anion, RS À ) to form an SNO derivative (R-SNO). Such modification modulates the function of a broad spectrum of extracellular, cytoplasmic, membrane, and nuclear proteins.…”

Section: Protein S-nitrosylation Affects Neuronal Survivalmentioning

confidence: 99%

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S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

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Section: Future Therapeutics: Nitromemantinesmentioning

confidence: 76%

Section: Protein S-nitrosylation Affects Neuronal Survivalmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

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“…Mouse cerebrocortical cultures from littermate WT and KO animals were prepared from embryos, as described previously, except that no cytostatic drugs were used. [47][48][49] Rat cultures, which had been studied previously and characterized, were used for experiments where only WT for both chemokine receptors was required. 11,31 Both types of cultures contained neurons, astrocytes, and microglia, and their composition has been described in detail.…”

Section: Methodsmentioning

confidence: 99%

“…11,31 Both types of cultures contained neurons, astrocytes, and microglia, and their composition has been described in detail. 47,48 Although the CXCR4 À/À phenotype is lethal at approximately E18, the isolated cerebrocortical cells survived well in vitro. Double KO embryos for cerebrocortical cultures were generated by crossbreeding mice deficient in both CXCR4 and CCR5 (in the case of CXCR4, using exclusively heterozygotes for breeding).…”

Section: Methodsmentioning

confidence: 99%

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HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/ gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1b and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca 2 þ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca 2 þ . This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.

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Subcellular localization of nitric oxide synthase in the cerebral ventricular system, subfornical organ, area postrema, and blood vessels of the rat brain

et al. 1997

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The distribution of neuronal nitric oxide synthase (nNOS) has been studied in the more rostral portion of the lateral ventricle, subfornical organ, area postrema and blood vessels of the rat central nervous system. nNOS was located by means of a specific polyclonal antibody, by using light and electron microscopy. Light microscopy showed immunoreactive varicose nerve fibers and terminal boutons-like structures in the lateral ventricle, positioned in supra- and subependimal areas. The spatial relationships between immunoreactive neuronal processes and the wall of the intracerebral blood vessels were studied. Electron microscopy showed numerous nerve fibers in the wall of the lateral ventricle; many were nNos-immunoreactive and established very close contact with ependymal cells. Immunoreactive neurons and processes were found in the subependymal plate of the ventricular wall, the subfornical organ, the area postrema, and the circularis nucleus of the hypothalamus. In these last three areas, the immunoreactive neurons were found close to the perivascular space of fenestrated and nonfenestrated blood vessels. The nNOS immunoreactivity was localized to the endoplasmic reticulum, cisterns, ribosomes, neurotubules, and in the inner part of the external membrane. In the terminal boutons, the reaction product was found surrounding the vesicle membranes. This distribution showed nNOS as a predominantly membrane-bound protein. The nitrergic nerve fibers present in the wall of the ventricular system might regulate metabolic functions as well as neurotransmission in the subfornical organ, area postrema and circularis nucleus of the hypothalamus.

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Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex

Cited by 720 publications

References 47 publications

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

Subcellular localization of nitric oxide synthase in the cerebral ventricular system, subfornical organ, area postrema, and blood vessels of the rat brain

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