Glutamate transporter and receptor function in disorders of ammonia metabolism.
Disorders of ammonia metabolism including urea cycle enzymopathies, Reye Syndrome, and liver failure are associated with brain edema and severe neurological impairment. Excess blood-borne ammonia crosses the blood-brain barrier by diffusion as NH(3) where it interacts with various cellular processes involved in neurotransmission and brain energy metabolism. Ammonia exerts a potent effect on glutamate (AMPA) receptor-mediated neurotransmission. Ammonia also inhibits high affinity transport of glutamate by an action on astrocytic glutamate transporter expression, an action which results in increased extracellular concentrations of glutamate. Acute hyperammonemia directly activates the NMDA subclass of glutamate receptors resulting in increased intracellular Ca(2+) and increased synthesis of nitric oxide and cGMP. Chronic hyperammonemia, on the other hand, results in a loss of NMDA receptor sites. Activation of NMDA receptors in acute ammonia toxicity results in depletion of ATP in brain. Neuropathologic studies in experimental animals with congenital urea cycle disorders and severe hyperammonemia reveal evidence of neuronal cell death which is excitotoxic in nature. These findings suggest that overactivation of NMDA receptors is a significant feature of acute hyperammonemic syndromes and that antagonists of these receptors or of their signal transduction pathway enzymes such as nNOS could be beneficial in the treatment of the central nervous system manifestations (encephalopathy, brain edema) which are characteristic of hyperammonemic disorders.
Butterworth
R F
RF
Neuroscience Research Unit, Hôpital Saint-Luc (C.H.U.M.), Montreal, Quebec, Canada. roger.butterworth@umontreal.ca
D000255:Adenosine Triphosphate / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D001928:Brain Diseases, Metabolic / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014508:Urea / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D027342:Excitatory Amino Acid Transporter 2; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D000641:Ammonia; D000255:Adenosine Triphosphate; D014508:Urea