Evaluation of the mechanism underlying the inhibitory effect of guanidinoacetate on brain Na+, K+-ATPase activity.
Guanidinoacetate methyltransferase deficiency (GAMT-deficiency) is an inherited neurometabolic disorder clinically characterized by epilepsy and mental retardation and biochemically by accumulation of guanidinoacetate (GAA) and depletion of creatine. Although the neurological symptoms are predominant, the pathogenesis of the brain dysfunction in this disorder is not yet established. In the present study we investigated the in vitro effect of GAA on Na+, K+-ATPase and Mg2+-ATPase activities in synaptic plasma membrane from hippocampus of young rats. Results showed that GAA significantly inhibited Na+, K+-ATPase activity without affecting Mg2+-ATPase activity. We also evaluated the effect of glutathione (GSH), trolox, Nomega-nitro-L-arginine methyl ester (L-NAME) and taurine (Tau) on the inhibition elicited by GAA on Na+, K+-ATPase activity. GSH, trolox, L-NAME and Tau per se did not alter Na+, K+-ATPase activity. However, L-NAME and taurine prevented the inhibitory effect of GAA on this enzyme activity. Our findings suggest that the inhibition of Na+, K+-ATPase activity caused by GAA is possibly mediated by nitric oxide (NO) formation and/or synaptic membrane alteration. The present data may contribute to the understanding of the neurological dysfunction characteristic of GAMT-deficient patients.
Zugno
Alexandra I
AI
Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Franzon
Renata
R
Chiarani
Fábria
F
Bavaresco
Caren S
CS
Wannmacher
Clovis M D
CM
Wajner
Moacir
M
Wyse
Angela T S
AT
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050937:Guanidinoacetate N-Methyltransferase; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013570:Synaptic Membranes / Q000187:drug effects / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016875:tau Proteins / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D016875:tau Proteins; C494508:Gamt protein, rat; D050937:Guanidinoacetate N-Methyltransferase; D017301:Ca(2+) Mg(2+)-ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; C004946:glycocyamine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester