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Division of Child Development and Rehabilitation, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318
This review
focuses on the role of acute pH changes in the regulation of Gln/Glu
metabolism in the kidney, liver, and brain. Alterations of proton
concentration ([H+])
profoundly affect flux through phosphate-dependent glutaminase (PDG) or
glutamate dehydrogenase (GDH), the primary enzymes
responsible for mitochondrial metabolism of glutamine and glutamate,
respectively. In the kidney, acute acidosis stimulates Gln uptake and
its metabolism via the PDG pathway. The Glu formed from Gln can be
removed via 1) oxidative deamination
through the GDH reaction, 2)
transamination reactions, and 3)
transport of Glu from intracellular to extracellular compartment,
thereby diminishing the intramitochondrial pool of glutamate
sufficiently to stimulate flux through the PDG pathway. Converse
changes may occur with increased pH. In the liver, acidosis diminishes
the rate of Gln and Glu metabolism via the PDG and GDH pathways, but
stimulates glutamine synthesis (i.e., glutamine recycling). Alkalosis
has little effect. Hepatic Gln metabolism via the PDG pathway has a
central role in ureagenesis via 1)
supplementation of nitrogen for the synthesis of carbamyl
phosphate, and 2)
providing glutamate for
N-acetylglutamate synthesis. In the
brain, Gln/Glu metabolism links ammonia detoxification and energy
metabolism via 1) detoxification of
ammonia and excess glutamate by glutamine synthesis in astrocytes,
2) formation and export of glutamine to neurons where it is metabolized to glutamate and GABA, and 3) production of 
-ketoglutarate
and lactate from Glu and their transport to neurons. Changes in
intracellular pH associated with changes in cellular
[K+] may have a key
role in the regulation of these processes of glial-neuronal metabolism
of Gln/Glu metabolism.
astrocytes; kidney; liver; neurons; tricarboxylic acid cycle; urea cycle
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