Mechanism of Mn(II)-mediated dysregulation of glutamine-glutamate cycle: Focus on glutamate turnover

Marta Sidoryk-Wegrzynowicz, Eunsook Lee, Michael Aschner

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Manganese (Mn) has been implicated in the impairment of the glutamate-glutamine cycling (GGC) by deregulation of Glu and glutamine (Gln) turnover in astrocytes. Here, we have examined possible mechanisms involved in the Mn(II)-mediated disruption of Glu turnover, including those related to protein degradation, such as the proteasomal and lysosomal machinery. Our study revealed that lysosome but not proteasomal inhibition is responsible for down-regulation of the Glu transporter after Mn(II) treatment. Because protein kinase C (PKC) activation leads to the down-regulation of Glu carriers, and Mn(II) increases PKC activity, we hypothesized that the PKC signaling contributes to the Mn(II)-mediated disruption of Glu turnover. Our results show that PKC activation causes a decrease in Glu uptake and that inhibition of PKC reverses Mn(II)-dependent down-regulation of Glu influx as well as glutamate transporter 1 (GLT1) and glutamate-aspartate transporter (GLAST) protein level. Co-immunoprecipitation studies show association of GLT1 with the PKCδ and PKCα isoforms and Mn(II)-induced specific increase in PKCδ-GLT1 interaction. In addition, astrocytes transfected with shRNA against PKCδ show decreased sensitivity to Mn(II) compared with those transfected with control shRNA or shRNA targeted against PKCα. Taken together, these findings demonstrate that PKCδ signaling is involved in the Mn(II)-induced deregulation of Glu turnover in astrocytes.

Original languageEnglish (US)
Pages (from-to)856-867
Number of pages12
JournalJournal of Neurochemistry
Volume122
Issue number4
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Manganese
Glutamine
Protein Kinase C
Glutamic Acid
Amino Acid Transport System X-AG
Astrocytes
Small Interfering RNA
Deregulation
Down-Regulation
Excitatory Amino Acid Transporter 1
Chemical activation
Lysosomes
Immunoprecipitation
Proteolysis
Machinery
Protein Isoforms
Proteins
Association reactions
Degradation

Keywords

  • GGC
  • GLAST
  • GLT1
  • manganese
  • PKC signaling

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Mechanism of Mn(II)-mediated dysregulation of glutamine-glutamate cycle : Focus on glutamate turnover. / Sidoryk-Wegrzynowicz, Marta; Lee, Eunsook; Aschner, Michael.

In: Journal of Neurochemistry, Vol. 122, No. 4, 08.2012, p. 856-867.

Research output: Contribution to journalArticle

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