In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage
Article first published online: 13 FEB 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 109, Issue 2, pages 551–561, April 2009
How to Cite
Erdmann, N., Tian, C., Huang, Y., Zhao, J., Herek, S., Curthoys, N. and Zheng, J. (2009), In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage. Journal of Neurochemistry, 109: 551–561. doi: 10.1111/j.1471-4159.2009.05989.x
- Issue published online: 18 MAR 2009
- Article first published online: 13 FEB 2009
- Received September 7, 2008; revised manuscript received February 3, 2009; accepted February 3, 2009.
- human immunodeficiency virus-1-associated dementia;
Mononuclear phagocyte (MP, macrophages and microglia) dysfunction plays a significant role in the pathogenesis of HIV-1-associated dementia (HAD) through the production and release of soluble neurotoxic factors including glutamate. Glutamate production is greatly increased following HIV-1 infection of cultured MP, a process dependent upon the glutamate-generating enzyme glutaminase. Glutaminase inhibition was previously found to significantly decrease macrophage-mediated neurotoxicity. Potential mechanisms of glutaminase-mediated excitotoxicity including enzyme up-regulation, increased enzyme activity and glutaminase localization were investigated in this report. RNA and protein analysis of HIV-infected human primary macrophage revealed up-regulation of the glutaminase isoform GAC, yet identified no changes in the kidney-type glutaminase isoform over the course of infection. Glutaminase is a mitochondrial protein, but was found to be released into the cytosol and extracellular space following infection. This released enzyme is capable of rapidly converting the abundant extracellular amino acid glutamine into excitotoxic levels of glutamate in an energetically favorable process. These findings support glutaminase as a potential component of the HAD pathogenic process and identify a possible therapeutic avenue for the treatment of neuroinflammatory states such as HAD.