Novel role of KCNQ2/3 channels in regulating neuronal cell viability

Cell Death Differ. 2011 Mar;18(3):493-505. doi: 10.1038/cdd.2010.120. Epub 2010 Oct 1.


Overactivation of certain K(+) channels can mediate excessive K(+) efflux and intracellular K(+) depletion, which are early ionic events in apoptotic cascade. The present investigation examined a possible role of the KCNQ2/3 channel or M-channel (also named Kv7.2/7.3 channels) in the pro-apoptotic process. Whole-cell recordings detected much larger M-currents (212 ± 31 pA or 10.5 ± 1.5 pA/pF) in cultured hippocampal neurons than that in cultured cortical neurons (47 ± 21 pA or 2.4 ± 0.8 pA/pF). KCNQ2/3 channel openers N-ethylmaleimide (NEM) and flupirtine caused dose-dependent K(+) efflux, intracellular K(+) depletion, and cell death in hippocampal cultures, whereas little cell death was induced by NEM in cortical cultures. The NEM-induced cell death was antagonized by co-applied KCNQ channel inhibitor XE991 (10 μM), or by elevated extracellular K(+) concentration. Supporting a mediating role of KCNQ2/3 channels in apoptosis, expression of KCNQ2 or KCNQ2/3 channels in Chinese hamster ovary (CHO) cells initiated caspase-3 activation. Consistently, application of NEM (20 μM, 8 h) in hippocampal cultures similarly caused caspase-3 activation assessed by immunocytochemical staining and western blotting. NEM increased the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), induced mitochondria membrane depolarization, cytochrome c release, formation of apoptosome complex, and apoptosis-inducing factor (AIF) translocation into nuclear. All these events were attenuated by blocking KCNQ2/3 channels. These findings provide novel evidence that KCNQ2/3 channels could be an important regulator in neuronal apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Inducing Factor / metabolism
  • Apoptosomes / metabolism
  • CHO Cells
  • Caspase 3 / metabolism
  • Cell Nucleus / metabolism
  • Cell Survival
  • Cricetinae
  • Cricetulus
  • Cytochromes c / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / cytology
  • Ion Channel Gating
  • KCNQ2 Potassium Channel / metabolism*
  • KCNQ3 Potassium Channel / metabolism*
  • Membrane Potential, Mitochondrial
  • Mice
  • Neurons / cytology*
  • Neurons / enzymology
  • Neurons / metabolism*
  • Protein Transport


  • Apoptosis Inducing Factor
  • Apoptosomes
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • Cytochromes c
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 3