Inhibition of synaptosomal [3H]glutamate uptake and [3H]glutamate binding to plasma membranes from brain of young rats by glutaric acid in vitro.
Synaptosomes and plasma membrane preparations from brain of 30-day-old rats were incubated with glutaric acid at final concentrations ranging from 10 nM to 1 mM for the determination of glutamate uptake and binding, respectively. [3H]Glutamate uptake into synaptosomes was inhibited by approximately 50% by 1 mM glutaric acid, corresponding to the concentration found in brain of glutaric acidemic children. In addition, in the presence of extracellular Na+ concentrations, the same dose of glutaric acid decreased by about 30% [3H]glutamate binding to brain plasma membranes. The results indicate that the inhibition of both glutamate uptake into synaptosomes and glutamate binding to plasma synaptic membranes by the metabolite could result in elevated concentrations of the excitatory neurotransmitter in the synaptic cleft, potentially causing excitotoxicity to neural cells, a fact that may be related to the brain damage characteristic of glutaric acidemia type I.
Porciúncula
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LO
Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre, Brazil.
Dal-Pizzol
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A
Coitinho
A S
AS
Emanuelli
T
T
Souza
D O
DO
Wajner
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M
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003292:Convulsants / Q000494:pharmacology*; D003864:Depression, Chemical; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D005977:Glutarates / Q000494:pharmacology*; D050770:Glutaryl-CoA Dehydrogenase; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009498:Neurotoxins / Q000494:pharmacology*; D010088:Oxidoreductases / Q000172:deficiency; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis / Q000172:deficiency
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D003292:Convulsants; D005977:Glutarates; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D050770:Glutaryl-CoA Dehydrogenase; D005968:Glutamate Decarboxylase; C035736:glutaric acid