Document Detail


In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling.
MedLine Citation:
PMID:  9122259     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cerebral tricarboxylic acid (TCA) cycle rate and the rate of glutamine synthesis were measured in rats in vivo under normal physiological and hyperammonemic conditions using 13C NMR spectroscopy. In the hyperammonemic animals, blood ammonia levels were raised from control values of approximately 0.05 mM to approximately 0.35 mM by an intravenous ammonium acetate infusion. Once a steady-state of cerebral metabolites was established, a [1-13C]glucose infusion was initiated, and 13C NMR spectra acquired continuously on a 7-tesla spectrometer to monitor 13C labeling of cerebral metabolites. The time courses of glutamate and glutamine C-4 labeling were fitted to a mathematical model to yield TCA cycle rate (V(TCA)) and the flux from glutamate to glutamine through the glutamine synthetase pathway (V(gln)). Under hyperammonemia the value of V(TCA) was 0.57 +/- 0.16 micromol/min per g (mean +/- SD, n = 6) and was not significantly different (unpaired t test; P > 0.10) from that measured in the control animals (0.46 +/- 0.12 micromol/min per g, n = 5). Therefore, the TCA cycle rate was not significantly altered by hyperammonemia. The measured rate of glutamine synthesis under hyperammonemia was 0.43 +/- 0.14 micromol/min per g (mean +/- SD, n = 6), which was significantly higher (unpaired t test; P < 0.01) than that measured in the control group (0.21 +/- 0.04 micromol/ min per g, n = 5). We propose that the majority of the glutamine synthetase flux under normal physiological conditions results from neurotransmitter substrate cycling between neurons and glia. Under hyperammonemia the observed increase in glutamine synthesis is comparable to the expected increase in ammonia transport into the brain and reported measurements of glutamine efflux under such conditions. Thus, under conditions of elevated plasma ammonia an increase in the rate of glutamine synthesis occurs as a means of ammonia detoxification, and this is superimposed on the constant rate of neurotransmitter cycling through glutamine synthetase.
Authors:
N R Sibson; A Dhankhar; G F Mason; K L Behar; D L Rothman; R G Shulman
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  94     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1997 Mar 
Date Detail:
Created Date:  1997-04-24     Completed Date:  1997-04-24     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2699-704     Citation Subset:  IM    
Affiliation:
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520-8043, USA. sibson@mrcbs.med.yale.edu
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MeSH Terms
Descriptor/Qualifier:
Ammonia / pharmacology
Animals
Brain / drug effects,  metabolism*
Carbon Isotopes
Citric Acid Cycle*
Glucose / metabolism*
Glutamate-Ammonia Ligase / metabolism
Glutamic Acid / metabolism*
Glutamine / metabolism*
Kinetics
Magnetic Resonance Spectroscopy
Male
Models, Chemical
Models, Theoretical
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
1 RO1-NS34813/NS/NINDS NIH HHS; R01-DK27121/DK/NIDDK NIH HHS; R29 NS32126-02/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Carbon Isotopes; 50-99-7/Glucose; 56-85-9/Glutamine; 56-86-0/Glutamic Acid; 7664-41-7/Ammonia; EC 6.3.1.2/Glutamate-Ammonia Ligase
Comments/Corrections

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


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