Редактирование: KCNB1 (раздел)

==Publications==

{{medline-entry
|title=Oxidation of [[KCNB1]] potassium channels in the murine brain during aging is associated with cognitive impairment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30922570
|abstract=Voltage-gated potassium (K ) channel sub-family B member 1 ([[KCNB1]], Kv2.1) is known to undergo oxidation-induced oligomerization during aging but whether this process affects brain's physiology was not known. Here, we used 10, 16 and 22 month-old transgenic mice overexpressing a [[KCNB1]] variant that does not oligomerize (Tg-C73A) and as control, mice overexpressing the wild type (Tg-WT) channel and non-transgenic (non-Tg) mice to elucidate the effects of channel's oxidation on cognitive function. Aging mice in which [[KCNB1]] oligomerization is negligible (Tg-C73A), performed significantly better in the Morris Water Maze (MWM) test of working memory compared to non-Tg or Tg-WT mice. [[KCNB1]] and synapsin-1 co-immunoprecipitated and the cognitive impairment in the MWM was associated with moderate loss of synapsin-1 in pre-synaptic structures of the hippocampus, whereas neurodegeneration and neuronal loss were not significantly different in the various genotypes. We conclude that moderate oxidation of the [[KCNB1]] channel during aging can influence neuronal networks by affecting synaptic function.
|mesh-terms=* Aging
* Animals
* Cognitive Dysfunction
* Gene Expression
* Genetic Variation
* Humans
* Memory, Short-Term
* Mice
* Mice, Transgenic
* Oxidation-Reduction
* Oxidative Stress
* Protein Multimerization
* Shab Potassium Channels

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471606
}}
{{medline-entry
|title=Oxidation of [[KCNB1]] Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27798188
|abstract=The delayed rectifier potassium (K ) channel [[KCNB1]] (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human [[KCNB1]] wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized [[KCNB1]] channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, a Food and Drug Administration-approved inhibitor of Src tyrosine kinases, was used to impinge on the proapoptotic signaling pathway activated by oxidized [[KCNB1]] channels. Thus, typical lesions of brain injury, namely, inflammation (astrocytosis), neurodegeneration, and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of [[KCNB1]] channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI. This study provides the first experimental evidence that oxidation of a K  channel constitutes a mechanism of neuronal and cognitive impairment in vertebrates. Specifically, the interaction of [[KCNB1]] channels with reactive oxygen species plays a major role in the etiology of mouse model of traumatic brain injury (TBI), a condition associated with extensive oxidative stress. In addition, a Food and Drug Administration-approved drug ameliorates the outcome of TBI in mouse, by directly impinging on the toxic pathway activated in response to oxidation of the [[KCNB1]] channel. These findings elucidate a basic mechanism of neurotoxicity in vertebrates and might lead to a new therapeutic approach to TBI in humans, which, despite significant efforts, is a condition that remains without effective pharmacological treatments.
|mesh-terms=* Animals
* Apoptosis
* Brain Injuries, Traumatic
* Cognition Disorders
* Dasatinib
* Hippocampus
* Male
* Mice
* Mice, Transgenic
* Neurodegenerative Diseases
* Neurons
* Oxidation-Reduction
* Oxidative Stress
* Protein Kinase Inhibitors
* Reactive Oxygen Species
* Shab Potassium Channels
|keywords=* Kv2.1
* ROS
* Src kinases
* aging
* dasatinib
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098843
}}
{{medline-entry
|title=Oxidation of K( ) Channels in Aging and Neurodegeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27114846
|abstract=Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels-which are key to neuronal excitability-in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. From this arose the idea that oxidation of ion channels by ROS is one of the culprits for neuronal aging. Aging-dependent oxidative modification of voltage-gated potassium (K( )) channels was initially demonstrated in the nematode Caenorhabditis elegans and more recently in the mammalian brain. Specifically, oxidation of the delayed rectifier [[KCNB1]] (Kv2.1) and of Ca(2 )- and voltage sensitive K( ) channels have been established suggesting that their redox sensitivity contributes to altered excitability, progression of healthy aging and of neurodegenerative disease. Here I discuss the implications that oxidation of K( ) channels by ROS may have for normal aging, as well as for neurodegenerative disease. 

|keywords=* K  channel
* ROS
* aging
* endothelial cells
* neurodegenerative disease
* neuron
* smooth muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809605
}}
{{medline-entry
|title=Oxidation of [[KCNB1]] K( ) channels in central nervous system and beyond.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24921000
|abstract=[[KCNB1]], a voltage-gated potassium (K( )) channel that conducts a major delayed rectifier current in the brain, pancreas and cardiovascular system is a key player in apoptotic programs associated with oxidative stress. As a result, this protein represents a bona fide drug target for limiting the toxic effects of oxygen radicals. Until recently the consensus view was that reactive oxygen species trigger a pro-apoptotic surge in [[KCNB1]] current via phosphorylation and SNARE-dependent incorporation of [[KCNB1]] channels into the plasma membrane. However, new evidence shows that [[KCNB1]] can be modified by oxidants and that oxidized [[KCNB1]] channels can directly activate pro-apoptotic signaling pathways. Hence, a more articulated picture of the pro-apoptotic role of [[KCNB1]] is emerging in which the protein induces cell's death through distinct molecular mechanisms and activation of multiple pathways. In this review article we discuss the diverse functional, toxic and protective roles that [[KCNB1]] channels play in the major organs where they are expressed. 

|keywords=* Aging
* Alzheimer’s disease
* Apoptosis
* Kv2.1
* Reactive oxygen species
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050120
}}
{{medline-entry
|title=Molecular mechanisms underlying the apoptotic effect of [[KCNB1]] K  channel oxidation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23275378
|abstract=Potassium (K( )) channels are targets of reactive oxygen species in the aging nervous system. [[KCNB1]] (formerly Kv2.1), a voltage-gated K( ) channel abundantly expressed in the cortex and hippocampus, is oxidized in the brains of aging mice and of the triple transgenic 3xTg-AD mouse model of Alzheimer's disease. [[KCNB1]] oxidation acts to enhance apoptosis in mammalian cell lines, whereas a [[KCNB1]] variant resistant to oxidative modification, C73A-[[KCNB1]], is cytoprotective. Here we investigated the molecular mechanisms through which oxidized [[KCNB1]] channels promote apoptosis. Biochemical evidence showed that oxidized [[KCNB1]] channels, which form oligomers held together by disulfide bridges involving Cys-73, accumulated in the plasma membrane as a result of defective endocytosis. In contrast, C73A-mutant channels, which do not oligomerize, were normally internalized. [[KCNB1]] channels localize in lipid rafts, and their internalization was dynamin 2-dependent. Accordingly, cholesterol supplementation reduced apoptosis promoted by oxidation of [[KCNB1]]. In contrast, cholesterol depletion exacerbated apoptotic death in a [[KCNB1]]-independent fashion. Inhibition of raft-associating c-Src tyrosine kinase and downstream JNK kinase by pharmacological and molecular means suppressed the pro-apoptotic effect of [[KCNB1]] oxidation. Together, these data suggest that the accumulation of [[KCNB1]] oligomers in the membrane disrupts planar lipid raft integrity and causes apoptosis via activating the c-Src/JNK signaling pathway.
|mesh-terms=* Aging
* Alzheimer Disease
* Amino Acid Substitution
* Animals
* Apoptosis
* CSK Tyrosine-Protein Kinase
* Cell Line, Tumor
* Disease Models, Animal
* Dynamin II
* MAP Kinase Kinase 4
* MAP Kinase Signaling System
* Membrane Microdomains
* Mice
* Mice, Transgenic
* Mutation, Missense
* Oxidation-Reduction
* Protein Multimerization
* Shab Potassium Channels
* src-Family Kinases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567663
}}