title: Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury.
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.
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Wei
authors: W
authors: Yu
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Randika
authors: R
authors: Parakramaweera
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Shavonne
authors: S
authors: Teng
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Manasa
authors: 0000-0003-2355-4578
authors: M
authors: Gowda
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Yashsavi
authors: Y
authors: Sharad
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Smita
authors: S
authors: Thakker-Varia
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
authors: Janet
authors: J
authors: Alder
authors: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 federico.sesti@rutgers.edu.
authors: Federico
authors: F
authors: Sesti
mesh_terms: D000818:Animals; D017209:Apoptosis; D000070642:Brain Injuries, Traumatic / Q000473:pathology / Q000503:physiopathology*; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D000069439:Dasatinib / Q000008:administration & dosage; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051669:Shab Potassium Channels / Q000378:metabolism*
chemical_list: C496990:Kcnb1 protein, mouse; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D051669:Shab Potassium Channels; D000069439:Dasatinib
keywords: Kv2.1; ROS; Src kinases; aging; dasatinib; oxidative stress