Oxidative modification of M-type K(+) channels as a mechanism of cytoprotective neuronal silencing.
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.
Gamper
Nikita
N
Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA. n.gamper@leeds.ac.uk
Zaika
Oleg
O
Li
Yang
Y
Martin
Pamela
P
Hernandez
Ciria C
CC
Perez
Michael R
MR
Wang
Andrew Y C
AY
Jaffe
David B
DB
Shapiro
Mark S
MS
D000818:Animals; D016466:CHO Cells; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008959:Models, Neurological; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology
D051656:KCNQ Potassium Channels; D016877:Oxidants; D013549:Sweetening Agents; D006861:Hydrogen Peroxide; D005947:Glucose