Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity.
Ammonia enters the brain by diffusion from the blood or cerebrospinal fluid, or is formed in situ from the metabolism of endogenous nitrogen-containing substances. Despite its central importance in nitrogen homeostasis, excess ammonia is toxic to the central nervous system and its concentration in the brain must be kept low. This is accomplished by the high activity of glutamine synthetase, which is localized in astrocytes and which permits efficient detoxification of incoming or endogenously generated ammonia. The location also permits the operation of an intercellular glutamine cycle. In this cycle, glutamate released from nerve terminals is taken up by astrocytes where it is converted to glutamine. Glutamine is released to the extracellular fluid to be taken up into the nerve cells, where it is converted back to glutamate by the action of glutaminase. Most extrahepatic organs lack a complete urea cycle, and for many organs, including the brain, glutamine represents a temporary storage form of waste nitrogen. As such, glutamine was long thought to be harmless to the brain. However, recent evidence suggests that excess glutamine is neurotoxic. Hyperammonemic syndromes (e.g., liver disease, inborn errors of the urea cycle, Reye's disease) consistently cause astrocyte pathology. Evidence has been presented that hyperammonemia results in increased formation of glutamine directly in astrocytes, thereby generating an osmotic stress to these cells. This osmotic stress results in impaired astrocyte function, which in turn leads to neuronal dysfunction. In this review a brief overview is presented of the role of glutamine in normal brain metabolism and in the pathogenesis of hyperammonemic syndromes.
Cooper
A J
AJ
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA. acooper@burke.org
D000641:Ammonia / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000502:physiology*; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D009997:Osmotic Pressure
D009498:Neurotoxins; D005973:Glutamine; D018698:Glutamic Acid; D000641:Ammonia; D009584:Nitrogen