Oxidative modification of M-type K+ channels as a mechanism of cytoprotective neuronal silencing

Nikita Gamper, Oleg Zaika, Yang Li, Pamela Martin, Ciria C. Hernandez, Michael R. Perez, Andrew Y.C. Wang, David B. Jaffe, Mark S. Shapiro

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Voltage-gated K+ channels of the Kv7 family underlie the neuronal M current that regulates action potential firing. Suppression of M current increases excitability and its enhancement can silence neurons. We here show that three of five Kv7 channels undergo strong enhancement of their activity by oxidative modification induced by physiological concentrations of hydrogen peroxide. A triple cysteine pocket in the channel S2-S3 linker is critical for this effect. Oxidation-induced enhancement of M current produced a hyperpolarization and a dramatic reduction of action potential firing frequency in rat sympathetic neurons. As hydrogen peroxide is robustly produced during hypoxia-induced oxidative stress, we used an oxygen/glucose deprivation neurodegeneration model that showed neuronal death to be severely accelerated by M current blockade. Such blockade had no effect on survival of normoxic neurons. This work describes a novel pathway of M-channel regulation and suggests a role for M channels in protective neuronal silencing during oxidative stress.

Original languageEnglish (US)
Pages (from-to)4996-5004
Number of pages9
JournalEMBO Journal
Volume25
Issue number20
DOIs
StatePublished - Oct 18 2006

Keywords

  • Cysteine
  • KCNQ
  • Kv7
  • Neurodegeneration
  • ROS

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Gamper, N., Zaika, O., Li, Y., Martin, P., Hernandez, C. C., Perez, M. R., Wang, A. Y. C., Jaffe, D. B., & Shapiro, M. S. (2006). Oxidative modification of M-type K+ channels as a mechanism of cytoprotective neuronal silencing. EMBO Journal, 25(20), 4996-5004. https://doi.org/10.1038/sj.emboj.7601374