Metallothionein-III prevents glutamate and nitric oxide neurotoxicity in primary cultures of cerebellar neurons

Carmina Montoliu, Pilar Monfort, Javier Carrasco, Òscar Palacios, Mercè Capdevila, Juan Hidalgo, Vicente Felipo

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Abstract

Metallothionein (MT)-III, a member of the MT family of metal-binding proteins, is mainly expressed in the CNS and is abundant in glutamatergic neurons. Results in genetically altered mice indicate that MT-III may play neuroprotective roles in the brain, but the mechanisms through which this protein functions have not been elucidated. The aim of this work was to assess whether MT-III is able to prevent glutamate neurotoxicity and to identify the step of the neurotoxic process interfered with by MT-III. Glutamate neurotoxicity in cerebellar neurons in culture is mediated by excessive activation of glutamate receptors, increased intracellular calcium, and increased nitric oxide. It is shown that MT-III prevented glutamate- and nitric oxide-induced neurotoxicity in a dose-dependent manner, with nearly complete protection at 0.3-1 μg/ml. MT-III did not prevent the glutamate- induced rise of intracellular calcium level but reduced significantly the nitric oxide-induced formation of cyclic GMP. Circular dichroism analysis revealed that nitric oxide triggers the release of the metals coordinated to the cysteine residues of MT-III, indicative of the S(Cys)-nitrosylation of the protein. Therefore, the present results indicate that MT-III can quench pathological levels of nitric oxide, thus preventing glutamate and nitric oxide neurotoxicity.
Original languageEnglish
Pages (from-to)266-273
JournalJournal of Neurochemistry
Volume75
Issue number1
DOIs
Publication statusPublished - 11 Jul 2000

Keywords

  • Cyclic GMP
  • Glutamate
  • Metallothionein-III
  • Neuroprotection
  • Neurotoxicity
  • Nitric oxide
  • Nitrosylation

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