Impairment of glutamine/ glutamate-γ-aminobutyric acid cycle in manganese toxicity in the central nervous system

Marta Sidoryk-Wegrzynowicz, Michael Aschner

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Glutamine metabolism in the healthy brain initiates a complex chain of metabolic events, including synthesis of the neurotransmitter amino acids glutamate and g-aminobutyric acid. Accordingly, disrupted glutamine turnover may affect the amino acid neurotransmitter balance, the disturbances of which contribute to the neuropathologic manifestations of manganism. Manganism has been considered as a metabolic syndrome related to impairment of glutamate transport and more recent glutamine/glutamate-g-aminobutyric acid cycle. In vivo and in vitro studies demonstrated that Mn evokes mitochondrial abnomalities, oxidative/nitrosative stress, and morphological/functional changes of astrocytes, a major component of the GGC cycle. Mn effectively increases abnormalities in the glutamine metabolism and turnover between glia and neurons. In vitro research revealed that Mn significantly decreases the activity of the major carrier of Glu-SNAT3 via the ubiquitination-dependent mechanisms. In addition, Mn mediates disruption of glutamate uptake from the synapse increasing the chances of glutamate-mediated excitotoxicity to surrounding neurons. There appear to be common signalling targets of Mn in GGC cycling in glial cells. Namely, the PKC signalling is affected by Mn in glutamine and glutamate transporters expression and function. The evidences described here not only contribute to understanding the mechanism by which Mn disrupts astrocytes function and astrocyte-neurons intercommunication, but may also potentially lead to the development of novel therapeutic interventions in animal models of manganese toxicity.

Original languageEnglish (US)
Pages (from-to)279-296
Number of pages18
JournalIssues in Toxicology
Issue number22
StatePublished - 2015

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis


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