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Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis.

Aoyama K, Nakaki T - Int J Mol Sci (2012)

Bottom Line: EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18).Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain.This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan; E-Mail: kaoyama@med.teikyo-u.ac.jp.

ABSTRACT
Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate-limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.

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Related in: MedlinePlus

Glutathione (GSH) as an antioxidant. Hydrogen peroxide (H2O2) and hydroperoxides (ROOH) are degraded by GSH peroxidase (GPx) to water and alcohols, respectively. GSH disulfide (GSSG), the oxidized form of GSH, is reduced back to GSH by the reaction of GSH reductase (GR) with NADPH. Catalase can remove H2O2 but not ROOH under normal physiological conditions. GSH conjugates with various endogenous and xenobiotic compounds (X), mediated by GSH-S-transferase (GST) to remove X from the cell. GSH can also react non-enzymatically with superoxide (O2•−), nitric oxide (NO), hydroxyl radical (•OH), and peroxynitrite (ONOO−).
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f1-ijms-13-12017: Glutathione (GSH) as an antioxidant. Hydrogen peroxide (H2O2) and hydroperoxides (ROOH) are degraded by GSH peroxidase (GPx) to water and alcohols, respectively. GSH disulfide (GSSG), the oxidized form of GSH, is reduced back to GSH by the reaction of GSH reductase (GR) with NADPH. Catalase can remove H2O2 but not ROOH under normal physiological conditions. GSH conjugates with various endogenous and xenobiotic compounds (X), mediated by GSH-S-transferase (GST) to remove X from the cell. GSH can also react non-enzymatically with superoxide (O2•−), nitric oxide (NO), hydroxyl radical (•OH), and peroxynitrite (ONOO−).

Mentions: GSH reacts non-enzymatically with superoxide, nitric oxide, hydroxyl radical, and peroxynitrite as an antioxidant [6] (Figure 1). Superoxide is generated by mitochondria in the process of ATP production. Superoxide or nitric oxide per se are not toxic unless they react with each other to form peroxynitrite [7], which is a potent oxidant in the brain [8]. Hydroxyl radicals form another potent oxidant, produced from hydrogen peroxide (H2O2) via the Fenton reaction or peroxynitrite decomposition [7,9], although the reaction rate of hydroxyl radical production is slow and the diffusion distance of hydroxyl radical is limited to much less than that of peroxynitrite [10]. GSH reacts directly with these oxidants to inhibit oxidative stress in the cell. In addition, GSH reacts enzymatically with GSH peroxidase (GPx) and GSH-S-transferase (GST) against neurodegeneration [6]. GPx requires GSH as electron donor to react with H2O2, which is produced from superoxide catalyzed by superoxide dismutase, or endogenous hydroperoxides, which are formed by lipid peroxidation [11]. In the process of peroxide disposal, GSH is oxidized to GSH disulfide (GSSG), which is then reduced back to GSH by GSH reductase (GR) with NADPH (nicotinamide adenine dinucleotide phosphate-oxidase) [12]. In neurons, GR is sufficiently active to allow the quick reduction of the accumulated GSSG [13]. GST reacts with various xenobiotics to form GSH conjugation, leading to detoxication of the compounds and their excretion from the cell.


Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis.

Aoyama K, Nakaki T - Int J Mol Sci (2012)

Glutathione (GSH) as an antioxidant. Hydrogen peroxide (H2O2) and hydroperoxides (ROOH) are degraded by GSH peroxidase (GPx) to water and alcohols, respectively. GSH disulfide (GSSG), the oxidized form of GSH, is reduced back to GSH by the reaction of GSH reductase (GR) with NADPH. Catalase can remove H2O2 but not ROOH under normal physiological conditions. GSH conjugates with various endogenous and xenobiotic compounds (X), mediated by GSH-S-transferase (GST) to remove X from the cell. GSH can also react non-enzymatically with superoxide (O2•−), nitric oxide (NO), hydroxyl radical (•OH), and peroxynitrite (ONOO−).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472789&req=5

f1-ijms-13-12017: Glutathione (GSH) as an antioxidant. Hydrogen peroxide (H2O2) and hydroperoxides (ROOH) are degraded by GSH peroxidase (GPx) to water and alcohols, respectively. GSH disulfide (GSSG), the oxidized form of GSH, is reduced back to GSH by the reaction of GSH reductase (GR) with NADPH. Catalase can remove H2O2 but not ROOH under normal physiological conditions. GSH conjugates with various endogenous and xenobiotic compounds (X), mediated by GSH-S-transferase (GST) to remove X from the cell. GSH can also react non-enzymatically with superoxide (O2•−), nitric oxide (NO), hydroxyl radical (•OH), and peroxynitrite (ONOO−).
Mentions: GSH reacts non-enzymatically with superoxide, nitric oxide, hydroxyl radical, and peroxynitrite as an antioxidant [6] (Figure 1). Superoxide is generated by mitochondria in the process of ATP production. Superoxide or nitric oxide per se are not toxic unless they react with each other to form peroxynitrite [7], which is a potent oxidant in the brain [8]. Hydroxyl radicals form another potent oxidant, produced from hydrogen peroxide (H2O2) via the Fenton reaction or peroxynitrite decomposition [7,9], although the reaction rate of hydroxyl radical production is slow and the diffusion distance of hydroxyl radical is limited to much less than that of peroxynitrite [10]. GSH reacts directly with these oxidants to inhibit oxidative stress in the cell. In addition, GSH reacts enzymatically with GSH peroxidase (GPx) and GSH-S-transferase (GST) against neurodegeneration [6]. GPx requires GSH as electron donor to react with H2O2, which is produced from superoxide catalyzed by superoxide dismutase, or endogenous hydroperoxides, which are formed by lipid peroxidation [11]. In the process of peroxide disposal, GSH is oxidized to GSH disulfide (GSSG), which is then reduced back to GSH by GSH reductase (GR) with NADPH (nicotinamide adenine dinucleotide phosphate-oxidase) [12]. In neurons, GR is sufficiently active to allow the quick reduction of the accumulated GSSG [13]. GST reacts with various xenobiotics to form GSH conjugation, leading to detoxication of the compounds and their excretion from the cell.

Bottom Line: EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18).Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain.This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan; E-Mail: kaoyama@med.teikyo-u.ac.jp.

ABSTRACT
Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate-limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.

Show MeSH
Related in: MedlinePlus