Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation

Lipton, Stuart A.; Choi, Yun-Beom; Takahashi, Hiroto; Zhang, Dongxian; Li, Weizhong; Godzik, Adam; Bankston, Laurie A.

doi:10.1016/s0166-2236(02)02245-2

Cited by 341 publications

(256 citation statements)

References 40 publications

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“…The enhanced binding of glutamate and Zn 2 þ in turn causes the receptor to desensitize and, consequently, the ion channel to close. 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.…”

Section: Future Therapeutics: Nitromemantinesmentioning

confidence: 97%

“…6,8,9,12,14,16,17,[19][20][21][22]48 Over the past decade, accumulating evidence has suggested that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. 10,[49][50][51][52][53][54] Chemically, NO is often a good 'leaving group,' facilitating further oxidation of critical thiol to disulfide bonds among neighboring (vicinal) cysteine residues or, via reaction with ROS, to sulfenic (ÀSOH), sulfinic (ÀSO 2 H), or sulfonic (ÀSO 3 H) acid derivatization of the protein. 19,20,22,55 Alternatively, S-nitrosylation may possibly produce a nitroxyl disulfide, in which the NO group is shared by close cysteine thiols.…”

Section: Protein S-nitrosylation Affects Neuronal Survivalmentioning

confidence: 99%

“…In vitro studies using recombinant NR1 and NR2A subunits of the NMDA receptor showed that S-nitrosylation of the receptor decreased the amplitude of its responses. 6,8,10,64 The NMDA receptor can be polynitrosylated at five cysteine residues of the NMDA receptor: Cys744 and Cys798 of NR1, and Cys87, Cys320, and Cys399 of the NR2A subunit. 8 Of these, Cys399 of NR2A mediates the predominant inhibitory effect of S-nitrosylation.…”

Section: S-nitrosylation As a Potential Negative Regulator Of Excitotmentioning

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: 97%

Section: Protein S-nitrosylation Affects Neuronal Survivalmentioning

confidence: 99%

Section: S-nitrosylation As a Potential Negative Regulator Of Excitotmentioning

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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“…In particular, receptors composed of NR1:NR2A subunits were shown to have a highly reversible and rapid current potentiation by sulfhydryl redox agents, including GSH, acting on a specific redox site in NR2A (Kohr et al, 1994). The oxidation status of this redox site can affect the regulation of these receptors by spermine and protons, as well as the inhibition mediated by the high-affinity Zn 2+ site (Lipton et al, 2002). On the other hand, oxidation of receptors containing NR2C is slowly reversible (Kohr et al, 1994).…”

Section: Redox Dysregulation Of Nmda-r Mediated Transmission In Pv-inmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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“…Indirect trans-nitrosation by NOS via intermediate scaffold and adaptor proteins was summarized by Hess et al [8]. They described how the N-methyl-D-aspartate (NMDA) receptor is S-nitrosated by neuronal NOS [30] via postsynaptic density protein 95 (PSD95), which serves as a scaffold. PSD95 is known to interaction with both the neuronal NOS [31] as well as the NMDA receptor [32], supporting its role as a scaffold.…”

Section: Enzymatic Regulation Of Protein S-nitrosationmentioning

confidence: 99%

How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?

Wolhuter

Eaton

2017

Free Radical Biology and Medicine

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Over the last 25 years protein S-nitrosylation, also known more correctly as S-nitrosation, has been progressively implicated in virtually every nitric oxide-regulated process within the cardiovascular system. The current, widely-held paradigm is that S-nitrosylation plays an equivalent role as phosphorylation, providing a stable and controllable post-translational modification that directly regulates end-effector target proteins to elicit biological responses. However, this concept largely ignores the intrinsic instability of the nitrosothiol bond, which rapidly reacts with typically abundant thiol-containing molecules to generate more stable disulfide bonds. These protein disulfides, formed via a nitrosothiol intermediate redox state, are rationally anticipated to be the predominant endeffector modification that mediates functional alterations when cells encounter nitrosative stimuli. In this review we present evidence and explain our reasoning for arriving at this conclusion that may be controversial to some researchers in the field.

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Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation

Cited by 341 publications

References 40 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

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

How widespread is stable protein S-nitrosylation as an end-effector of protein regulation?

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