title: Oxidation of KCNB1 potassium channels triggers apoptotic integrin signaling in the brain.
abstract: Oxidative modification of the voltage-gated potassium (K+) channel KCNB1 promotes apoptosis in the neurons of cortex and hippocampus through a signaling pathway mediated by Src tyrosine kinases. How oxidation of the channel is transduced into Src recruitment and activation, however, was not known. Here we show that the apoptotic signal originates from integrins, which form macromolecular complexes with KCNB1 channels. The initial stimulus is transduced to Fyn and possibly other Src family members by focal adhesion kinase (FAK). Thus KCNB1 and integrin alpha chain V (integrin-α5) coimmunoprecipitated in the mouse brain and these interactions were retained upon channel's oxidation. Pharmacological inhibition of integrin signaling or FAK suppressed apoptosis induced by oxidation of KCNB1, as well as FAK and Src/Fyn activation. Most importantly, the activation of the integrin-FAK-Src/Fyn cascade was negligible in the presence of non-oxidizable C73A KCNB1 mutant channels, even though they normally interacted with integrin-α5. This leads us to conclude that the transition between the non-oxidized and oxidized state of KCNB1 activates integrin signaling. KCNB1 oxidation may favor integrin clustering, thereby facilitating the recruitment and activation of FAK and Src/Fyn kinases.
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, USA.
authors.forename: Manasa
authors.initials: M
authors.lastname: Gowda
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, USA.
authors.forename: Yashsavi
authors.initials: Y
authors.lastname: Sharad
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, USA.
authors.forename: Surindo A
authors.initials: SA
authors.lastname: Singh
authors.affiliation: Department of Neuroscience and Cell Biology, Rutgers University, Robert Wood Johnson Medical School, 683 Hoes Lane West, Piscataway, NJ, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Sesti
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D039482:Integrin alpha5; C496990:Kcnb1 protein, mouse; D051669:Shab Potassium Channels; D051417:Focal Adhesion Kinase 1; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases