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Is there In Vivo Evidence for Amino Acid Shuttles Carrying Ammonia from Neurons to Astrocytes?

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Abstract

The high in vivo flux of the glutamate/glutamine cycle puts a strong demand on the return of ammonia released by phosphate activated glutaminase from the neurons to the astrocytes in order to maintain nitrogen balance. In this paper we review several amino acid shuttles that have been proposed for balancing the nitrogen flows between neurons and astrocytes in the glutamate/glutamine cycle. All of these cycles depend on the directionality of glutamate dehydrogenase, catalyzing reductive glutamate synthesis (forward reaction) in the neuron in order to capture the ammonia released by phosphate activated glutaminase, while catalyzing oxidative deamination of glutamate (reverse reaction) in the astrocytes to release ammonia for glutamine synthesis. Reanalysis of results from in vivo experiments using 13N and 15N labeled ammonia and 15N leucine in rats suggests that the maximum flux of the alanine/lactate or branched chain amino acid/branched chain amino acid transaminase shuttles between neurons and astrocytes are approximately 3–5 times lower than would be required to account for the ammonia transfer from neurons to astrocytes needed for glutamine synthesis (amide nitrogen) to sustain the glutamate/glutamine cycle. However, in the rat brain both the total ammonia fixation rate by glutamate dehydrogenase and the total branched chain amino acid transaminase activity are sufficient to support a branched chain amino acid/branched chain keto acid shuttle, as proposed by Hutson and coworkers, which would support the de novo synthesis of glutamine in the astrocyte to replace the ~20 % of neurotransmitter glutamate that is oxidized. A higher fraction of the nitrogen needs of total glutamate neurotransmitter cycling could be supported by hybrid cycles in which glutamate and tricarboxylic acid cycle intermediates act as a nitrogen shuttle. A limitation of all in vivo studies in animals conducted to date is that none have shown transfer of nitrogen for glutamine amide synthesis, either as free ammonia or via an amino acid from the neurons to the astrocytes. Future work will be needed, perhaps using methods for selectively labeling nitrogen in neurons, to conclusively establish the rate of amino acid nitrogen shuttles in vivo and their coupling to the glutamate/glutamine cycle.

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Acknowledgments

The author’s would like to acknowledge the valuable suggestions by the reviewers and Gerald Dienel. In addition we acknowledge support from the National Institutes of Health 1R01AG034953-01A1 (DLR, HMDF) and R01MH095104 (KLB, DLR) and fellowship grant (#10A087) from AICR to HMDF. We also acknowledge Leif Hertz for his guidance, support, and insights over many years.

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Authors and Affiliations

  1. Department of Diagnostic Radiology and Biomedical Engineering, Magnetic Resonance Research Center, Yale University School of Medicine, 300 Cedar Street, P.O. Box 208043, New Haven, CT, 06520-8043, USA

    Douglas L. Rothman

  2. Department of Diagnostic Radiology, Magnetic Resonance Research Center, Yale University School of Medicine, 300 Cedar Street, P.O. Box 208043, New Haven, CT, 06520-8043, USA

    Henk M. De Feyter

  3. Department of Psychiatry, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA

    Paul K. Maciejewski

  4. Department of Psychiatry, Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, CT, USA

    Kevin L. Behar

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  1. Douglas L. Rothman
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  2. Henk M. De Feyter
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  3. Paul K. Maciejewski
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  4. Kevin L. Behar
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Correspondence to Douglas L. Rothman.

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Special Issue: In Honor of Dr. Leif Hertz.

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Rothman, D.L., De Feyter, H.M., Maciejewski, P.K. et al. Is there In Vivo Evidence for Amino Acid Shuttles Carrying Ammonia from Neurons to Astrocytes?. Neurochem Res 37, 2597–2612 (2012). https://doi.org/10.1007/s11064-012-0898-7

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  • DOI: https://doi.org/10.1007/s11064-012-0898-7

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