Utilization of Glutamine and of TCA Cycle Constituents as Precursors for Transmitter Glutamate and GABA

Abstract

In the present review evidence is presented that (1) glutamine synthesis in astrocytes is essential for synthesis of GABA in neurons; (2) α-ketoglutarate in the presence of alanine (as an amino group donor) can replace glutamine as a precursor for synthesis of transmitter glutamate, but maybe not as a precursor for transmitter GABA; (3) differences exist in the intraneuronal metabolic pathways for utilization of α-ketoglutarate plus alanine and of glutamine, and (4) alanine also functions as a substrate for oxidative metabolism in glutamatergic neurons. It should be emphasized that the supply of precursors for transmitter glutamate and GABA in glutamatergic and GABAergic neurons depends on metabolic processes in astrocytes regardless whether glutamine or α-ketoglutarate plus L-alanine function as the transmitter precursors. The key reason that an interaction with astrocytes is essential is that both pyruvate carboxylase, the major enzyme in the brain for net synthesis of tricarboxylic acid cycle intermediates, and glutamine synthetase, the enzyme forming glutamine from glutamate, are specifically located in astrocytes, but not in neurons.

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

“…Another possibility is that the downregulation of EAAT1 detected by Western blotting could limit the uptake of glutamate and therefore the synthesis and transport of glutamine from the glial cells to the GABAergic terminal, compromising the synthesis of GABA as well (29).…”

“…However, the behavioural phenotype could also be due to compensatory changes that occur in the VGLUT1+/-animals that leave the EPSC size unchanged. More specifically, the increase of the neuronal de novo synthesis of glutamate, derived from [1-13C]glucose, suggests a compensatory effect for the decreased vesicular VGLUT1 content and, perhaps, for the down-regulation of EAAT1 (29,(34)(35). This increase could contribute to the maintenance of both the cytoplasmic and the vesicular pools (36) of glutamate in the VGLUT1+/-neurons, which would agree with the normal tissue levels detected by HPLC and may be sufficient to normalize EPSC size.…”

Primary Structure, Genomic Organization, and Functional and Electrogenic Characteristics of Human System N 1, a Na+- and H+-coupled Glutamine Transporter

“…The transmembrane H ϩ gradient and the transmembrane glutamine gradient appear to be important in this context. Because periportal hepatocytes synthesize urea, which requires not only ammonia but also HCO 3 Ϫ , these cells have an effective means of HCO 3 Ϫ disposal. In contrast, perivenous hepatocytes remove ammonia via glutamine synthesis rather than urea synthesis, and this process does not involve HCO 3 Ϫ .…”

“…Because periportal hepatocytes synthesize urea, which requires not only ammonia but also HCO 3 Ϫ , these cells have an effective means of HCO 3 Ϫ disposal. In contrast, perivenous hepatocytes remove ammonia via glutamine synthesis rather than urea synthesis, and this process does not involve HCO 3 Ϫ . Thus, perivenous hepatocytes do not have an effective means of HCO 3 Ϫ disposal.…”

“…It plays an important role in ammonia metabolism (1), in the synthesis of purines and pyrimidines (2), and in the glutamine-glutamate cycle that occurs between neurons and glial cells in the brain (3,4) and between placenta and liver in the developing fetus (5). Glutamine is also an obligatory participant in the intercellular glutamine cycle that occurs in the liver between periportal hepatocytes and perivenous hepatocytes (6).…”