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

X. Zhou, J. Wei, M. Song, K. Francis, S. P. Yu

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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 (21231 pA or 10.51.5 pA/pF) in cultured hippocampal neurons than that in cultured cortical neurons (4721 pA or 2.40.8 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 M), 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 M, 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.

Original languageEnglish (US)
Pages (from-to)493-505
Number of pages13
JournalCell Death and Differentiation
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2011

Keywords

  • ERK1/2
  • KCNQ channel
  • Kv7 channel
  • M-current
  • apoptosis
  • neurons

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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