Brain ATP depletion induced by acute ammonia intoxication in rats is mediated by activation of the NMDA receptor and Na+,K(+)-ATPase.
Injection of large doses of ammonia into rats leads to depletion of brain ATP. However, the molecular mechanism leading to ATP depletion is not clear. The aim of the present work was to assess whether ammonium-induced depletion of ATP is mediated by activation of the NMDA receptor. It is shown that injection of MK-801, an antagonist of the NMDA receptor, prevented ammonia-induced ATP depletion but did not prevent changes in glutamine, glutamate, glycogen, glucose, and ketone bodies. Ammonia injection increased Na+,K(+)-ATPase activity by 76%. This increase was also prevented by previous injection of MK-801. The molecular mechanism leading to activation of the ATPase was further studied. Na+,K(+)-ATPase activity in samples from ammonia-injected rats was normalized by "in vitro" incubation with phorbol 12-myristate 13-acetate, an activator of protein kinase C. The results obtained suggest that ammonia-induced ATP depletion is mediated by activation of the NMDA receptor, which results in decreased protein kinase C-mediated phosphorylation of Na+,K(+)-ATPase and, therefore, increased activity of the ATPase and increased consumption of ATP.
Instituto de Investigaciones Citologicas de la Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
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E
Kosenko
Y
Y
Kaminsky
E
E
Grau
M D
MD
Miñana
G
G
Marcaida
S
S
Grisolía
V
V
Felipo
D000085:Acetates / Q000008:administration & dosage; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000641:Ammonia / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001986:Bronchial Spasm / Q000139:chemically induced; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005973:Glutamine / Q000096:biosynthesis; D006985:Hyperventilation / Q000139:chemically induced; D008297:Male; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D000085:Acetates; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D016291:Dizocilpine Maleate; D000641:Ammonia; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; C018824:ammonium acetate