Inhibition of GTRAP3-18 May Increase Neuroprotective Glutathione (GSH) Synthesis

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.

Influence of 6‐Hydroxydopamine Toxicity on α‐Synuclein Phosphorylation, Resting Vesicle Expression, and Vesicular Dopamine Release

“…As 6-OHDA is a potent oxidant, this apoptosis may be the result of an imbalance between the generation of reactive oxygen species and the antioxidant system. ROS can convert to superoxide radicals and/or hydrogen peroxide, which are respectively neutralized by SOD1 and GPx along with the substrate GSH [Aoyama and Nakaki, 2012]. The superoxide radicals in the presence of NADPH and nitric oxide synthase can further give rise to nitrite radical [Li et al, 2013].…”

Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus

“…There are a few possible explanations for the opposite effect in a seizure model. EAAC1 −/− mice display markedly decreased levels of the antioxidant glutathione, synthesized from glutamate and cysteine, both of which are transported into neurons by EAAC1 (Kanai and Hediger, 1992; Rothstein et al, 1994; Rothstein et al, 1996; Diamond, 2001; Sepkuty et al, 2002; Chen and Swanson, 2003; Himi et al, 2003; Mathews and Diamond, 2003; Aoyama et al, 2008; Scimemi et al, 2009; Escartin et al, 2011; Aoyama and Nakaki, 2012; Aoyama et al, 2012a). It is possible that maintenance of neuronal glutathione is more important for attenuating ischemia-mediated cell death than for attenuation of seizure-induced cell death.…”

“…Three main physiological functions have been attributed to EAAC1: limitation of spillover at excitatory synapses (Rothstein et al, 1994; Diamond, 2001; Scimemi et al, 2009), provision of glutamate for GABA synthesis (Sepkuty et al, 2002; Mathews and Diamond, 2003), and contribution to neuronal uptake of cysteine for synthesis of glutathione (Chen and Swanson, 2003; Himi et al, 2003; Aoyama et al, 2008; Escartin et al, 2011; Aoyama and Nakaki, 2012; Aoyama et al, 2012a; for reviews see Aoyama et al, 2012b; Aoyama and Nakaki, 2013). Most studies suggest that EAAC1 may be neuroprotective.…”

Análise da influência da restrição nutricional na modulação proteica de células de leucemia mielóide crônica (K562)

“…GSTs catalisam a conjugação de glutationa reduzida (GSH -) a uma vasta variedade de compostos eletrofílicos, a fim de os tornar mais solúveis permitindo a sua eliminação [130]. Como um resultado desta actividade de desintoxicação, GSTs protegem a célula contra os danos do DNA, a instabilidade genômica e o desenvolvimento do câncer.…”

“…Como um resultado desta actividade de desintoxicação, GSTs protegem a célula contra os danos do DNA, a instabilidade genômica e o desenvolvimento do câncer. Além disso, como as proteínas não-enzimáticas, as GSTs são capazes de modular vias que controlam a proliferação celular, diferenciação celular e apoptose, entre outros processos de sinalização [130]. Diferenças na atividade GSTs podem modificar o risco de desenvolvimento de câncer e também pode ter impacto sobre as respostas heterogêneas para substâncias tóxicas ou de terapias específicas .…”