Title: Mechanism of Mn(II)-mediated dysregulation of glutamine-glutamate cycle: focus on glutamate turnover.

Authors: Sidoryk-Wegrzynowicz, Marta; Lee, Eunsook; Aschner, Michael

Published In J Neurochem, (2012 Aug)

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 PKCýý and PKCýý isoforms and Mn(II)-induced specific increase in PKCýý-GLT1 interaction. In addition, astrocytes transfected with shRNA against PKCýý show decreased sensitivity to Mn(II) compared with those transfected with control shRNA or shRNA targeted against PKCýý. Taken together, these findings demonstrate that PKCýý signaling is involved in the Mn(II)-induced deregulation of Glu turnover in astrocytes.

PubMed ID: 22708868

MeSH Terms: No MeSH terms associated with this publication