Unbound MEDLINE

Toxic role of K+ channel oxidation in mammalian brain.

Abstract

Potassium (K(+)) channels are essential to neuronal signaling and survival. Here we show that these proteins are targets of reactive oxygen species in mammalian brain and that their oxidation contributes to neuropathy. Thus, the KCNB1 (Kv2.1) channel, which is abundantly expressed in cortex and hippocampus, formed oligomers upon exposure to oxidizing agents. These oligomers were ∼10-fold more abundant in the brain of old than young mice. Oxidant-induced oligomerization of wild-type KCNB1 enhanced apoptosis in neuronal cells subject to oxidative insults. Consequently, a KCNB1 variant resistant to oxidation, obtained by mutating a conserved cysteine to alanine, (C73A), was neuroprotective. The fact that oxidation of KCNB1 is toxic, argues that this mechanism may contribute to neuropathy in conditions characterized by high levels of oxidative stress, such as Alzheimer's disease (AD). Accordingly, oxidation of KCNB1 channels was exacerbated in the brain of a triple transgenic mouse model of AD (3xTg-AD). The C73A variant protected neuronal cells from apoptosis induced by incubation with β-amyloid peptide (Aβ(1-42)). In an invertebrate model (Caenorhabditis elegans) that mimics aspects of AD, a C73A-KCNB1 homolog (C113S-KVS-1) protected specific neurons from apoptotic death induced by ectopic expression of human Aβ(1-42). Together, these data underscore a novel mechanism of toxicity in neurodegenerative disease.

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  • Publisher Full Text
  • Authors

    Cotella D, Hernandez-Enriquez B, Wu X, Li R, Pan Z, Leveille J, Link CD, Oddo S, Sesti F

    Institution

    Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.

    Source

    The Journal of neuroscience : the official journal of the Society for Neuroscience 32:12 2012 Mar 21 pg 4133-44

    MeSH

    2,2'-Dipyridyl
    Age Factors
    Alanine
    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Analysis of Variance
    Animals
    Animals, Genetically Modified
    Apoptosis
    Brain
    Caenorhabditis elegans
    Cells, Cultured
    Cricetinae
    Cricetulus
    Cysteine
    Disease Models, Animal
    Disulfides
    Electric Stimulation
    Embryo, Mammalian
    Female
    Fluoresceins
    Humans
    Hydrogen Peroxide
    Male
    Mass Spectrometry
    Membrane Potentials
    Mice
    Neurons
    Oxidants
    Oxidation-Reduction
    Oxidative Stress
    Patch-Clamp Techniques
    Peptide Fragments
    Presenilin-1
    Propanols
    Shab Potassium Channels
    Transfection

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22442077