Nitrogen metabolism: Neuronal-astroglial relationships

M. Yudkoff, I. Nissim, L. Hertz, David E Pleasure, M. Erecinska

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The brain must be capable of both the rapid synthesis and the rapid disposal of glutamic acid (GLU), the major excitatory transmitter. A relatively abundant pool of GLU must be maintained in glutamatergic neurons, which constantly release this transmitter, and in GABAergic neurons, which decarboxylate GLU to GABA. In contrast, extracellular GLU must be kept very low in order to maximize the 'signal-to-noise' ratio upon release of GLU from pre-synaptic terminals and to avoid the toxicity that can occur if extracellular [GLU] is excessive. These goals are realized, in part, when astrocytes take up extracellular GLU via a high affinity transporter and convert it to glutamine (GLN), which then is released to neurons, where GLN is a precursor to GLU and GABA. Using the stable isotope 15N as a tracer, we have found that this so-called 'glutamate-glutamine cycle' oversimplifies astrocyte GLU metabolism, since pathways other than the glutamine synthetase reaction figure prominently. Thus, important roles are played by the glutamate dehydrogenase reaction, the purine nucleotide cycle, the gamma-glutamyl cycle and various transamination reactions. The latter, we have found, are especially prominent in astrocytes, in which the release of [15N]alanine after incubation with [15N]glutamate is quite active, and suggests that alanine could be transaminated to GLU in neurons. We confirmed this hypothesis in studies of [15N]alanine and [15N]leucine metabolism in cultured GABAergic neurons. Studies with 15NH4Cl indicated that these neurons produced little GLU via the reductive amination of 2-oxo-glutarate, at least at physiologic ammonia concentrations. A similar pattern was observed in synaptosomes incubated with 15NH4Cl. At high (3-5 mM) [NH4 +] the production of [15N]glutamate was much greater. GLN, of course, is a significant source of neuronal GLU, although it may not be the sole source. We used [2-15N]glutamine as a tracer to study glutamine metabolism in synaptosomes. We found that the glutaminase reaction, and not GLN transport, is rate-limiting for GLN metabolism. Depolarization diminished GLN uptake but augmented flux through glutaminase, probably by increasing mitochondrial [P(i)] from the breakdown of ATP and creatine phosphate. Flux through glutaminase was inhibited by high [H+] in the medium and was stimulated markedly at alkaline pH. These data underscore the richness of the astroglial-neuronal 'dialogue' with regard to GLU metabolism, which should not be reduced to a 'glutamate-glutamine cycle'. The data also have implications for human disease, since any clinical perturbation that might interfere with energy metabolism, e.g., hypoxia, or that would increase the size of a particular N pool, e.g., hyperammonemia, also would upset the skein of relationships that maintains normal brain glutamate metabolism.

Original languageEnglish (US)
Pages (from-to)213-224
Number of pages12
JournalProgress in Brain Research
Volume94
StatePublished - 1992
Externally publishedYes

Fingerprint

Glutamic Acid
Nitrogen
Glutamine
Glutaminase
Astrocytes
Alanine
Neurons
GABAergic Neurons
Synaptosomes
gamma-Aminobutyric Acid
Glutarates
Purine Nucleotides
Hyperammonemia
Amination
Glutamate Dehydrogenase
Glutamate-Ammonia Ligase
Phosphocreatine
Presynaptic Terminals
Brain
Signal-To-Noise Ratio

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Yudkoff, M., Nissim, I., Hertz, L., Pleasure, D. E., & Erecinska, M. (1992). Nitrogen metabolism: Neuronal-astroglial relationships. Progress in Brain Research, 94, 213-224.

Nitrogen metabolism : Neuronal-astroglial relationships. / Yudkoff, M.; Nissim, I.; Hertz, L.; Pleasure, David E; Erecinska, M.

In: Progress in Brain Research, Vol. 94, 1992, p. 213-224.

Research output: Contribution to journalArticle

Yudkoff, M, Nissim, I, Hertz, L, Pleasure, DE & Erecinska, M 1992, 'Nitrogen metabolism: Neuronal-astroglial relationships', Progress in Brain Research, vol. 94, pp. 213-224.
Yudkoff M, Nissim I, Hertz L, Pleasure DE, Erecinska M. Nitrogen metabolism: Neuronal-astroglial relationships. Progress in Brain Research. 1992;94:213-224.
Yudkoff, M. ; Nissim, I. ; Hertz, L. ; Pleasure, David E ; Erecinska, M. / Nitrogen metabolism : Neuronal-astroglial relationships. In: Progress in Brain Research. 1992 ; Vol. 94. pp. 213-224.
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