Regulation of glutamine synthetase in normal and injured neural tissues

Abstract

Glutamine synthetase (GS) constitutes an endogenous mechanism for protection against glutamate neurotoxicity in neural tissues by catalyzing the amidation of the neurotoxic amino acid glutamate to the non-toxic amino acid glutamine. Expression of GS is regulated by systemic glucocorticoids, which induce transcription of the GS gene in glial cells only. This cell type specificity is established through the mutual activity of positive and negative regulatory elements, the glucocorticoid response element (GRE) and the neural restrictive silencing element (NRSE), respectively. Glial cell proliferation, which often occurs at the site of neural injury (gliosis), results in a marked decline in GS expression. This decline is mediated by the c-Jun protein, which accumulates in the proliferating cells and blocks the transcriptional activity of the glucocorticoid receptor. Disruption of glia-neuron cell contacts or supply of bFGF can also cause a decline in GS by a mechanism that involves the activation of the c-Jun signaling pathway in glial cells. Considering the detoxificating role of GS, stimulation of glial cell proliferation at the site of injury may exacerbate glutamate-mediated neurotoxicity through direct downregulation of GS.