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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Brain/*metabolism ; Glutathione/*biosynthesis ; Heat-Shock Proteins/*antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/*antagonists & inhibitors ; Neurodegenerative Diseases/*drug therapy ; Neurons/*metabolism ; Neuroprotective Agents/*therapeutic use; Animals ; Brain/pathology ; Excitatory Amino Acid Transporter 3/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Transport Proteins ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurons/pathology

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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Keywords: EAAC1; GTRAP3-18; cysteine uptake; glutathione; neurodegeneration
Note: Original DateCompleted: 20121031

0 (ARL6IP5 protein, human)
0 (Excitatory Amino Acid Transporter 3)
0 (Heat-Shock Proteins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Membrane Transport Proteins)
0 (Neuroprotective Agents)
0 (SLC1A1 protein, human)
GAN16C9B8O (Glutathione)

Date Created: 20121031 Date Completed: 20150821 Latest Revision: 20220922

20250114

PMC3472789

10.3390/ijms130912017

23109897