Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1

Mark L Dallas, John P Boyle, Carol J Milligan, Rachael Sayer, Talitha L Kerrigan, Connor McKinstry, Peiyuan Lu, Jamel Mankouri, Mark Harris, Jason L Scragg, Hugh A Pearson, Chris Peers

Research output: Contribution to journalArticle (Academic Journal)peer-review

63 Citations (Scopus)

Abstract

Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, and age-related neurodegenerative diseases. An early step in this process is the loss of intracellular K(+) via K(+) channels, and evidence indicates that K(v)2.1 is of particular importance in this regard, being rapidly inserted into the plasma membrane in response to apoptotic stimuli. An additional feature of neuronal oxidative stress is the up-regulation of the inducible enzyme heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe(2+), and carbon monoxide (CO). CO provides neuronal protection against stresses such as stroke and excitotoxicity, although the underlying mechanisms are not yet elucidated. Here, we demonstrate that CO reversibly inhibits K(v)2.1. Channel inhibition by CO involves reactive oxygen species and protein kinase G activity. Overexpression of K(v)2.1 in HEK293 cells increases their vulnerability to oxidant-induced apoptosis, and this is reversed by CO. In hippocampal neurons, CO selectively inhibits K(v)2.1, reverses the dramatic oxidant-induced increase in K(+) current density, and provides marked protection against oxidant-induced apoptosis. Our results provide a novel mechanism to account for the neuroprotective effects of CO against oxidative apoptosis, which has potential for therapeutic exploitation to provide neuronal protection in situations of oxidative stress.

Original languageEnglish
Pages (from-to)1519-30
Number of pages12
JournalFASEB Journal
Volume25
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • 2,2'-Dipyridyl
  • Animals
  • Apoptosis
  • Carbon Monoxide
  • Caspase 3
  • Caspase 7
  • Cell Line
  • Disulfides
  • Electrophysiology
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Oxidants
  • Rats
  • Rats, Wistar
  • Shab Potassium Channels

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