In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage

Authors

  • Nathan Erdmann,

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
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  • Changhai Tian,

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
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  • Yunlong Huang,

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
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  • Jianxing Zhao,

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
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  • Shelley Herek,

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
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  • Norman Curthoys,

    1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, USA
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  • Jialin Zheng

    1. Laboratory of Neurotoxicology at the Center for Neurovirology and Neurodegenerative Disorders, Omaha, Nebraska, USA
    2. Department of Pharmacology/Experimental Neuroscience, Omaha, Nebraska, USA
    3. Department of Pathology/Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Address correspondence and reprint requests to Dr Jialin Zheng, Laboratory of Neurotoxicology, Center for Neurovirology and Neurodegenerative Disorders and Departments of Pharmacology/Experimental Neuroscience and Pathology/Microbiology, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA. E-mail: jzheng@unmc.edu

Abstract

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.

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