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Chloride-dependent inhibition of vesicular glutamate uptake by alpha-keto acids accumulated in maple syrup urine disease.

Abstract
Maple syrup urine disease is a metabolic disorder caused by mutations of the branched chain keto acid dehydrogenase complex, leading to accumulation of alpha-keto acids and their amino acid precursors in the brain. We now report that alpha-ketoisovaleric, alpha-keto-beta-methyl-n-valeric and alpha-ketoisocaproic acids accumulated in the disease inhibit glutamate uptake into rat brain synaptic vesicles. The alpha-keto acids did not affect the electrochemical proton gradient across the membrane, suggesting that they interact directly with the vesicular glutamate carrier. Chloride anions have a biphasic effect on glutamate uptake. Low concentrations activate the uptake (0.2 to 8 mM), while higher concentrations are inhibitory. The alpha-keto acids inhibited glutamate uptake by a new mechanism, involving a change in the chloride dependence for the activation of glutamate uptake. The activation of glutamate uptake by low chloride concentrations was shifted toward higher concentrations of the anion in the presence of alpha-keto acids. Inhibition by alpha-keto acids was abolished at high chloride concentrations (20 to 80 mM), indicating that alpha-keto acids specifically change the stimulatory effect of low chloride concentrations. High glutamate concentrations also reduced the inhibition by alpha-keto acids, an effect observed both in the absence and in the presence of low chloride concentrations. The results suggest that in addition to their possible pathophysiological role in maple syrup urine disease, alpha-keto acids are valuable tools to study the mechanism of vesicular transport of glutamate.
AuthorsM Reis, M Farage, H Wolosker
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1475 Issue 2 Pg. 114-8 (Jul 03 2000) ISSN: 0006-3002 [Print] Netherlands
PMID10832024 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATP-Binding Cassette Transporters
  • Amino Acid Transport System X-AG
  • Chlorides
  • Hemiterpenes
  • Keto Acids
  • alpha-keto-beta-methylvaleric acid
  • Glutamic Acid
  • alpha-ketoisovalerate
  • alpha-ketoisocaproic acid
Topics
  • ATP-Binding Cassette Transporters (metabolism)
  • Amino Acid Transport System X-AG
  • Animals
  • Biological Transport (drug effects)
  • Brain (metabolism)
  • Cell Membrane (metabolism)
  • Chlorides (pharmacology)
  • Electrochemistry
  • Glutamic Acid (metabolism)
  • Hemiterpenes
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Keto Acids (metabolism, pharmacology)
  • Maple Syrup Urine Disease (etiology)
  • Membrane Potentials
  • Rats
  • Synaptic Vesicles (drug effects, metabolism)

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