Deletion of TRAAK potassium channel affects brain metabolism and protects against ischemia

PLoS One. 2012;7(12):e53266. doi: 10.1371/journal.pone.0053266. Epub 2012 Dec 28.

Abstract

Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K⁺ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K⁺ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak⁻/⁻ mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak⁻/⁻ mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak⁺/⁺ mice. Upon ischemia, Traak⁻/⁻ mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak⁺/⁺ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak⁻/⁻ mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Cytoprotection / genetics
  • Energy Metabolism / genetics
  • Female
  • Gene Deletion
  • Hypoxia-Ischemia, Brain / complications
  • Hypoxia-Ischemia, Brain / diagnostic imaging
  • Hypoxia-Ischemia, Brain / genetics*
  • Hypoxia-Ischemia, Brain / prevention & control
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / diagnostic imaging
  • Infarction, Middle Cerebral Artery / genetics
  • Infarction, Middle Cerebral Artery / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Potassium Channels / genetics*
  • Radiography

Substances

  • Kcnk4 protein, mouse
  • Potassium Channels

Grants and funding

This work was supported by the National Center for Scientific Research (CNRS) and Aix-Marseille University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.