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Department of Pediatrics, University of Pennsylvania School of Medicine, Childrens Hospital of Philadelphia, Philadelphia, PA 19104-4318
3To whom correspondence should be addressed.
Intrasynaptic [glutamate] must be kept low in order to maximize the
signal-to-noise ratio after the release of transmitter glutamate. This
is accomplished by rapid uptake of glutamate into astrocytes, which
convert glutamate into glutamine. The latter then is released to
neurons, which, via mitochondrial glutaminase, form the glutamate that
is used for neurotransmission. This pattern of metabolic
compartmentation is the "glutamate-glutamine cycle." This model is
subject to the following two important qualifications:
1) brain avidly oxidizes glutamate via aspartate
aminotransferase; and 2) because almost no glutamate crosses from blood
to brain, it must be synthesized in the central nervous system (CNS).
The primary source of glutamate carbon is glucose, and a major source
of glutamate nitrogen is the branched-chain amino acids, which are
transported rapidly into the CNS. This arrangement accomplishes the
following: 1) maintenance of low external [glutamate],
thereby maximizing signal-to-noise ratio upon depolarization;
2) the replenishing of the neuronal glutamate pool;
3) the "trafficking" of glutamate through the
extracellular fluid in a nonneuroactive form (glutamine);
4) the importation of amino groups from blood, thus
maintaining brain nitrogen homeostasis; and 5) the
oxidation of glutamate/glutamine, a process that confers an additional
level of control in terms of the regulation of brain glutamate,
aspartate and
-aminobutyric acid.
KEY WORDS: glutamate glutamine branched-chain amino acids glucose transport metabolism neuron glia brain
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