title: 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.
authors.affiliation: Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Cotella
authors.forename: Berenice
authors.initials: B
authors.lastname: Hernandez-Enriquez
authors.forename: Xilong
authors.initials: X
authors.lastname: Wu
authors.forename: Ruiqiong
authors.initials: R
authors.lastname: Li
authors.forename: Zui
authors.initials: Z
authors.lastname: Pan
authors.forename: Joseph
authors.initials: J
authors.lastname: Leveille
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Link
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Federico
authors.initials: F
authors.lastname: Sesti
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000633:toxicity; D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000166:cytology*; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003545:Cysteine / Q000235:genetics; D004195:Disease Models, Animal; D004220:Disulfides / Q000633:toxicity; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D005260:Female; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1 / Q000235:genetics; D020005:Propanols / Q000494:pharmacology; D051669:Shab Potassium Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D006845:Hydrocarbons, Fluorinated
chemical_list: D015082:2,2'-Dipyridyl; D000409:Alanine; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003545:Cysteine; D004220:Disulfides; D005452:Fluoresceins; D006861:Hydrogen Peroxide; D016877:Oxidants; D010446:Peptide Fragments; D053764:Presenilin-1; D020005:Propanols; D051669:Shab Potassium Channels; C508853:PSEN1 protein, human; C075222:amyloid beta-protein (1-42); C029569:diacetyldichlorofluorescein; C001105:2,2'-dipyridyl disulfide; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated