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  • The EMBO Journal (2006) 25, 4996 - 5004
  • doi:10.1038/sj.emboj.7601374

Published online: 5 October 2006

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

Nikita Gamper1,3, Oleg Zaika1, Yang Li1, Pamela Martin1, Ciria C Hernandez1, Michael R Perez2, Andrew YC Wang2, David B Jaffe2 and Mark S Shapiro1

  1. Department of Physiology, University of Texas Health Science Center, San Antonio, TX, USA
  2. Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA
  3. Institute of Membrane and Systems Biology, University of Leeds, Leeds, UK

Correspondence to:

Nikita Gamper, Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, UK. Tel.: +44 (0)113 343 7923; Fax: +44 (0)113 343 3167; E-mail: n.gamper@leeds.ac.uk

Mark S Shapiro, Department of Physiology, UT Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Tel.: +(210) 567 4328; Fax: +(210) 567 4410; E-mail: shapirom@uthscsa.edu

Received 28 June 2006; Accepted 6 September 2006

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.

  • Keywords:

    • cysteine,
    • KCNQ,
    • Kv7,
    • neurodegeneration,
    • ROS