Effect of ammonia on astrocytic glutamate uptake/release mechanisms.
Hyperammonemic disorders such as acute liver failure (ALF) or urea cycle enzymopathies are associated with hyperexcitability, seizures, brain edema and increased extracellular brain glutamate. Mechanisms responsible for increased glutamate content in the extracellular space of the brain include decreased uptake by perineuronal astrocytes and/or increased release from neurons and/or astrocytes. Exposure of astrocytes to millimolar concentrations of ammonia results in cell swelling, loss of expression of the glutamate transporters excitatory amino acid transporter (EAAT-1) and EAAT-2 and increased release of glutamate. Three distinct mechanisms are theoretically possible to explain ammonia-induced glutamate release from astrocytes namely: release due to swelling; reversal of glutamate transporters and due to Ca2+-dependent vesicular release. Recent identification of vesicular docking and fusion proteins in astrocytes together with glutamate-release (due to intracellular alkanization and mobilization of intracellular Ca2+-stores) studies implies that vesicular release is a predominant mechanism responsible for ammonia-induced release of glutamate from astrocytes.
Rose
Christopher
C
Max-Delbrück Center for Molecular Medicine, Department of Cellular Neurosciences, Berlin, Germany. christopherrose99@yahoo.ca
D000641:Ammonia / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D027341:Excitatory Amino Acid Transporter 1 / Q000187:drug effects; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000209:etiology / Q000378:metabolism; D017114:Liver Failure, Acute / Q000150:complications
D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D000641:Ammonia; D002118:Calcium