Document Detail

Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes?
MedLine Citation:
PMID:  23104556     Owner:  NLM     Status:  MEDLINE    
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 (13)N and (15)N labeled ammonia and (15)N 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.
Douglas L Rothman; Henk M De Feyter; Paul K Maciejewski; Kevin L Behar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2012-10-27
Journal Detail:
Title:  Neurochemical research     Volume:  37     ISSN:  1573-6903     ISO Abbreviation:  Neurochem. Res.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-05     Completed Date:  2013-04-23     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7613461     Medline TA:  Neurochem Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2597-612     Citation Subset:  IM    
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MeSH Terms
Amino Acids / metabolism*
Ammonia / metabolism*
Astrocytes / metabolism*
Biological Transport
Neurons / metabolism*
Nitrogen / metabolism
Grant Support
1R01AG034953-01A1/AG/NIA NIH HHS; R01 AG034953/AG/NIA NIH HHS; R01 MH095104/MH/NIMH NIH HHS; R01MH095104/MH/NIMH NIH HHS
Reg. No./Substance:
0/Amino Acids; 7664-41-7/Ammonia; N762921K75/Nitrogen

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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