Glutamine in the Central Nervous System: Function and Dysfunction

Glutamine (Gln) abounds in the central nervous system (CNS), and its interstitial and cerebrospinal fluid (CSF) concentrations are at least one order of magnitude higher than of any other amino acid. Gln transport from blood to the brain is insufficient to meet the demand of the brain tissues for this amino acid. This demand is met by intracerebral Gln synthesis from glutamate (Glu), a reaction carried out by glutamine synthetase (GS), an enzyme residing in astrocytes. A major proportion of astroglia-derived Gln is shuttled to neurons where it is degraded by phosphate-activated glutaminase (PAG) giving rise to the excitatory neurotransmitter amino acid Glu, which is also a precursor of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Glu released from neurons is taken up by astrocytes, and reconverted to Gln, closing the so called "glutamate-glutamine" cycle. A portion of Gln serves as an energy metabolite, and part of it leaves the brain to blood. Gln efflux from astrocytes, its neuronal uptake and egress to the blood via the cerebral capillary endothelial cells is mediated by different amino acid carriers showing i) considerable preference for Gln, ii) distribution between astrocytes and neurons that favors astrocyte-to-neuron fluxes of the amino acid. The Gln-specific carriers also largely contribute to Gln efflux from the brain to the vascular bed. Excessive accumulation of Gln in brain cells may be deleterious to brain function. In hyperammonemia associated with acute liver failure, excess Gln leads to cerebral edema, which largely results from its interference with mitochondrial function and partly from its osmotic action. Future analyses of the roles of Gln in both normal and abnormal cerebral metabolism and function will have to account for its newly recognized direct involvement in the regulation of gene transcription and/or translation.