Toxic Role of K+ Channel Oxidation in Mammalian Brain

Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2012; 32(12):4133-44. DOI: 10.1523/JNEUROSCI.6153-11.2012
Source: PubMed


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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    • "Hydrogen peroxide exposure has been shown to directly oxidize Kv2.1 channels, leading to channel oligomerization and downstream apoptosis. Importantly, an oxidation-resistant Kv2.1 channel cysteine mutant (C73A) that prevents oligomerization also attenuates toxicity induced by Aβ exposure (Cotella et al., 2012). Interestingly, enhanced oligomerization of Kv2.1 is also observed in a mouse model of AD, although how this change in Kv2.1 structure contributes to AD-related cognition decline was not determined (Cotella et al., 2012). "
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    ABSTRACT: Brain aging is marked by structural, chemical, and genetic changes leading to cognitive decline and impaired neural functioning. Further, aging itself is also a risk factor for a number of neurodegenerative disorders, most notably Alzheimer's disease (AD). Many of the pathological changes associated with aging and aging-related disorders have been attributed in part to increased and unregulated production of reactive oxygen species (ROS) in the brain. ROS are produced as a physiological byproduct of various cellular processes, and are normally detoxified by enzymes and antioxidants to help maintain neuronal homeostasis. However, cellular injury can cause excessive ROS production, triggering a state of oxidative stress that can lead to neuronal cell death. ROS and intracellular zinc are intimately related, as ROS production can lead to oxidation of proteins that normally bind the metal, thereby causing the liberation of zinc in cytoplasmic compartments. Similarly, not only can zinc impair mitochondrial function, leading to excess ROS production, but it can also activate a variety of extra-mitochondrial ROS-generating signaling cascades. As such, numerous accounts of oxidative neuronal injury by ROS-producing sources appear to also require zinc. We suggest that zinc deregulation is a common, perhaps ubiquitous component of injurious oxidative processes in neurons. This review summarizes current findings on zinc dyshomeostasis-driven signaling cascades in oxidative stress and age-related neurodegeneration, with a focus on AD, in order to highlight the critical role of the intracellular liberation of the metal during oxidative neuronal injury.
    Full-text · Article · Apr 2014 · Frontiers in Aging Neuroscience
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    • "Recent work suggests that the spontaneous electrical activity of SCN neurons is very sensitive to changes in the redox state (Wang et al., 2012). In addition, it is worth noting that K+ channels are sensitive to oxidative damage (Sesti et al., 2010; Cotella et al., 2012). Increased daytime firing rates are dependent on K+ channel currents, and therefore oxidative damage to the channels, which are mediating these currents in the SCN, may underlie the reduced daytime firing rates observed in the 3-NP model. "
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    ABSTRACT: Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting the mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.
    Full-text · Article · Dec 2013 · ASN Neuro
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    • "The Kv channel protein family is the most diverse class of voltage-gated ion channels, boasting 40 known pore-forming α subunit genes in the human genome. With additional contribution from several classes of ancillary (β) subunits (Pongs and Schwarz, 2010), homomeric, and heteromeric α subunit complex formation (MacKinnon et al., 1993; Weiser et al., 1994; Rudy and McBain, 2001), and post-translational modifications including phosphorylation (Perozo and Bezanilla, 1991; Holmes et al., 1996a; Thomas et al., 1999), glycosylation (Freeman et al., 2000; Park et al., 2003; Brooks et al., 2006; Chandrasekhar et al., 2011), sumoylation (Dai et al., 2009), nitrosylation (Asada et al., 2009), and oxidation (Cai and Sesti, 2009; Sesti et al., 2010; Cotella et al., 2012), the number of potential combinations of functional Kv channel complexes, each with different functional properties, is staggering. Excitable and non-excitable cells alike exploit this embarrassment of riches to generate the specific repolarization profiles, regulatory responsiveness, and/or ionic gradients required for their cellular physiology. "
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    ABSTRACT: Voltage-gated potassium (Kv) channels shape the action potentials of excitable cells and regulate membrane potential and ion homeostasis in excitable and non-excitable cells. With 40 known members in the human genome and a variety of homomeric and heteromeric pore-forming α subunit interactions, post-translational modifications, cellular locations, and expression patterns, the functional repertoire of the Kv α subunit family is monumental. This versatility is amplified by a host of interacting proteins, including the single membrane-spanning KCNE ancillary subunits. Here, examining both the secretory and the endocytic pathways, we review recent findings illustrating the surprising virtuosity of the KCNE proteins in orchestrating not just the function, but also the composition, diaspora and retrieval of channels formed by their Kv α subunit partners.
    Preview · Article · Jun 2012 · Frontiers in Physiology
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