SK2 channels are neuroprotective for ischemia-induced neuronal cell death

J Cereb Blood Flow Metab. 2011 Dec;31(12):2302-12. doi: 10.1038/jcbfm.2011.90. Epub 2011 Jun 29.


In mouse hippocampal CA1 pyramidal neurons, the activity of synaptic small-conductance Ca(2+)-activated K(+) channels type 2 (SK2 channels) provides a negative feedback on N-methyl-D-aspartate receptors (NMDARs), reestablishing Mg(2+) block that reduces Ca(2+) influx. The well-established role of NMDARs in ischemia-induced excitotoxicity led us to test the neuroprotective effect of modulating SK2 channel activity following cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Administration of the SK channel positive modulator, 1-ethyl-benzimidazolinone (1-EBIO), significantly reduced CA1 neuron cell death and improved CA/CPR-induced cognitive outcome. Electrophysiological recordings showed that CA/CPR-induced ischemia caused delayed and sustained reduction of synaptic SK channel activity, and immunoelectron microscopy showed that this is associated with internalization of synaptic SK2 channels, which was prevented by 1-EBIO treatment. These results suggest that increasing SK2 channel activity, or preventing ischemia-induced loss of synaptic SK2 channels, are promising and novel approaches to neuroprotection following cerebral ischemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Benzimidazoles / pharmacology
  • Brain Ischemia / pathology*
  • Brain Ischemia / psychology
  • CA1 Region, Hippocampal / pathology
  • Cardiopulmonary Resuscitation
  • Cell Death
  • Heart Arrest / complications
  • Heart Arrest / pathology
  • Immunohistochemistry
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Immunoelectron
  • Motor Activity / physiology
  • Neurons / pathology
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • Pyramidal Cells / pathology
  • Recognition, Psychology / physiology
  • Small-Conductance Calcium-Activated Potassium Channels / genetics
  • Small-Conductance Calcium-Activated Potassium Channels / physiology*
  • Synapses / physiology
  • Synapses / ultrastructure


  • Benzimidazoles
  • Kcnn2 protein, mouse
  • Small-Conductance Calcium-Activated Potassium Channels
  • 1-ethyl-2-benzimidazolinone