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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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EAAC1/GTRAP3-18-mediated GSH synthesis in neurons. GSH is produced from three amino acids, i.e., glutamate (Glu), cysteine (Cys), and glycine (Gly) by reactions with two enzymes, γ-glutamylcysteine ligase (GCL) and GSH synthase (GS). Translocated to the plasma membrane, EAAC1 transports glutamate and cysteine into the neuron to increase GSH synthesis. Glutamate transporters, as the functioning forms, are present predominantly as trimers on the plasma membrane. SNAP-23 facilitates EAAC1 expression on the plasma membrane. EAAC1 is subject to internalization into early endosome and is recycled back to the plasma membrane in a Rab11-dependent manner. Rab1A regulates multiple membrane trafficking pathways. GTRAP3-18, a protein in the endoplasmic reticulum (ER), binds to Rab1A to interfere with the ER-Golgi transport of EAAC1. Moreover, GTRAP3-18 directly interacts with EAAC1 and retains EAAC1 at the ER to inhibit neuronal GSH synthesis. Arl6ip1 is a GTRAP3-18 interacting protein leading to decrease in GTRAP3-18/EAAC1 interaction. Arl6ip1 positively modulates EAAC1-mediated glutamate transport.
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f2-ijms-13-12017: EAAC1/GTRAP3-18-mediated GSH synthesis in neurons. GSH is produced from three amino acids, i.e., glutamate (Glu), cysteine (Cys), and glycine (Gly) by reactions with two enzymes, γ-glutamylcysteine ligase (GCL) and GSH synthase (GS). Translocated to the plasma membrane, EAAC1 transports glutamate and cysteine into the neuron to increase GSH synthesis. Glutamate transporters, as the functioning forms, are present predominantly as trimers on the plasma membrane. SNAP-23 facilitates EAAC1 expression on the plasma membrane. EAAC1 is subject to internalization into early endosome and is recycled back to the plasma membrane in a Rab11-dependent manner. Rab1A regulates multiple membrane trafficking pathways. GTRAP3-18, a protein in the endoplasmic reticulum (ER), binds to Rab1A to interfere with the ER-Golgi transport of EAAC1. Moreover, GTRAP3-18 directly interacts with EAAC1 and retains EAAC1 at the ER to inhibit neuronal GSH synthesis. Arl6ip1 is a GTRAP3-18 interacting protein leading to decrease in GTRAP3-18/EAAC1 interaction. Arl6ip1 positively modulates EAAC1-mediated glutamate transport.

Mentions: GSH synthesis consists of two consecutive enzymatic steps requiring ATP (Figure 2). The first step is the reaction of glutamate with cysteine catalyzed by glutamate cysteine ligase (GCL), and the second is the reaction of γ-glutamylcysteine with glycine catalyzed by GSH synthase (GS). In neurons, the availability of cysteine, but not that of glutamate or glycine, limits intracellular GSH levels [32]. Compared to the intracellular concentrations of glutamate and glycine, the cysteine concentration is maintained at much lower levels because of its toxicity to the cell [33–36]. The first step, i.e., the catalysis by GCL, is considered the rate-limiting reaction for GSH synthesis. The Km value of GCL for cysteine is 0.1–0.3 mM: that of glutamate is 1.8 mM [37]. The intracellular glutamate concentration is much higher than the Km value, whereas the intracellular cysteine level is around the Km value. Therefore, the intracellular cysteine level is considered the rate-limiting precursor for GSH synthesis.


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

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

EAAC1/GTRAP3-18-mediated GSH synthesis in neurons. GSH is produced from three amino acids, i.e., glutamate (Glu), cysteine (Cys), and glycine (Gly) by reactions with two enzymes, γ-glutamylcysteine ligase (GCL) and GSH synthase (GS). Translocated to the plasma membrane, EAAC1 transports glutamate and cysteine into the neuron to increase GSH synthesis. Glutamate transporters, as the functioning forms, are present predominantly as trimers on the plasma membrane. SNAP-23 facilitates EAAC1 expression on the plasma membrane. EAAC1 is subject to internalization into early endosome and is recycled back to the plasma membrane in a Rab11-dependent manner. Rab1A regulates multiple membrane trafficking pathways. GTRAP3-18, a protein in the endoplasmic reticulum (ER), binds to Rab1A to interfere with the ER-Golgi transport of EAAC1. Moreover, GTRAP3-18 directly interacts with EAAC1 and retains EAAC1 at the ER to inhibit neuronal GSH synthesis. Arl6ip1 is a GTRAP3-18 interacting protein leading to decrease in GTRAP3-18/EAAC1 interaction. Arl6ip1 positively modulates EAAC1-mediated glutamate transport.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ijms-13-12017: EAAC1/GTRAP3-18-mediated GSH synthesis in neurons. GSH is produced from three amino acids, i.e., glutamate (Glu), cysteine (Cys), and glycine (Gly) by reactions with two enzymes, γ-glutamylcysteine ligase (GCL) and GSH synthase (GS). Translocated to the plasma membrane, EAAC1 transports glutamate and cysteine into the neuron to increase GSH synthesis. Glutamate transporters, as the functioning forms, are present predominantly as trimers on the plasma membrane. SNAP-23 facilitates EAAC1 expression on the plasma membrane. EAAC1 is subject to internalization into early endosome and is recycled back to the plasma membrane in a Rab11-dependent manner. Rab1A regulates multiple membrane trafficking pathways. GTRAP3-18, a protein in the endoplasmic reticulum (ER), binds to Rab1A to interfere with the ER-Golgi transport of EAAC1. Moreover, GTRAP3-18 directly interacts with EAAC1 and retains EAAC1 at the ER to inhibit neuronal GSH synthesis. Arl6ip1 is a GTRAP3-18 interacting protein leading to decrease in GTRAP3-18/EAAC1 interaction. Arl6ip1 positively modulates EAAC1-mediated glutamate transport.
Mentions: GSH synthesis consists of two consecutive enzymatic steps requiring ATP (Figure 2). The first step is the reaction of glutamate with cysteine catalyzed by glutamate cysteine ligase (GCL), and the second is the reaction of γ-glutamylcysteine with glycine catalyzed by GSH synthase (GS). In neurons, the availability of cysteine, but not that of glutamate or glycine, limits intracellular GSH levels [32]. Compared to the intracellular concentrations of glutamate and glycine, the cysteine concentration is maintained at much lower levels because of its toxicity to the cell [33–36]. The first step, i.e., the catalysis by GCL, is considered the rate-limiting reaction for GSH synthesis. The Km value of GCL for cysteine is 0.1–0.3 mM: that of glutamate is 1.8 mM [37]. The intracellular glutamate concentration is much higher than the Km value, whereas the intracellular cysteine level is around the Km value. Therefore, the intracellular cysteine level is considered the rate-limiting precursor for GSH synthesis.

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