Low extracellular zinc increases neuronal oxidant production through nadph oxidase and nitric oxide synthase activation

Lucila Aimo, Gary N. Cherr, Patricia I. Oteiza

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

A decrease in zinc (Zn) levels increases the production of cell oxidants, affects the oxidant defense system and triggers oxidant sensitive signals in neuronal cells. However, the underlying mechanisms are still unclear. This work tested the hypothesis that the increase in neuronal oxidants that occurs when cellular Zn decreases is mediated by the activation of the NMDA receptor. Differentiated PC12 cells were cultured in control, Zn-deficient or Zn-repleted media. The incubation in Zn deficient media led to a rapid increase in cellular calcium levels, which was prevented by a NMDA receptor antagonist (MK-801). Cellular calcium accumulation was associated with NADPH oxidase and nitric oxide synthase (NOS) activation, an increase in cell oxidant levels, and an associated activation of a redox-sensitive signal (AP-1). In cells incubated in the Zn deficient medium, NADPH oxidase activation was prevented by MK-801 and by a protein kinase C inhibitor. The rise in cell oxidants was prevented by inhibitors of NADPH oxidase, of the NOS and by MK-801. A similar pattern of inhibitor action was observed for zinc deficiency-induced AP-1 activation. Results demonstrate that a decrease in extracellular Zn leads to an increase in neuronal oxidants through the activation of the NMDAR that leads to calcium influx and to a calcium-mediated activation of protein kinase C/NADPH oxidase and NOS. Changes in extracellular Zn concentrations can be sensed by neurons, which using reactive oxygen and nitrogen species as second messengers, can regulate signaling involved in neuronal development and function.

Original languageEnglish (US)
Pages (from-to)1577-1587
Number of pages11
JournalFree Radical Biology and Medicine
Volume48
Issue number12
DOIs
StatePublished - Jun 2010

Fingerprint

Oxidants
Nitric Oxide Synthase
Zinc
Oxidoreductases
Chemical activation
NADPH Oxidase
Dizocilpine Maleate
Calcium
Transcription Factor AP-1
N-Methyl-D-Aspartate Receptors
Protein Kinase C
Reactive Nitrogen Species
Protein C Inhibitor
PC12 Cells
Second Messenger Systems
Protein Kinase Inhibitors
Neurons
Oxidation-Reduction
Reactive Oxygen Species

Keywords

  • AP-1
  • NADPH oxidase
  • Neuron
  • NMDA receptor
  • NOS
  • Oxidants
  • Zinc
  • Zinc deficiency

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Low extracellular zinc increases neuronal oxidant production through nadph oxidase and nitric oxide synthase activation. / Aimo, Lucila; Cherr, Gary N.; Oteiza, Patricia I.

In: Free Radical Biology and Medicine, Vol. 48, No. 12, 06.2010, p. 1577-1587.

Research output: Contribution to journalArticle

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