Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Glutamine synthetase (GS) is involved in important processes in brain: modulation of the turnover of glutamate through the glutamate-glutamine cycle, detoxification of ammonia and, under certain circumstances, modulation of brain edema. Modulation of GS activity in brain is therefore important and its impairment or saturation may have pathological consequences. In this review we summarize the data showing that GS in brain is modulated by NMDA receptors and nitric oxide. Blocking NMDA receptors or nitric oxide synthase in vivo increases GS activity and glutamine content in brain, indicating that tonic activation of NMDA receptors and nitric oxide synthase maintain a tonic inhibition of GS. NMDA receptor-mediated activation of nitric oxide synthase is responsible only for part of the inhibition of GS. Other sources of nitric oxide also contribute to tonic inhibition. The inhibition is due to a covalent modification of GS, likely nitration of tyrosine residues. This modification would be reversible and it would be an enzyme that denitrosylate or denitrate GS. Moreover, GS would not be working at maximum rate and its activity may be increased pharmacologically by manipulating NMDA receptors or nitric oxide content. This may be useful for example to increase ammonia detoxification in brain in hyperammonemic situations.