Increased activity of plasma membrane K+ channels, leading to. decreased cytoplasmic K+ concentrations, occurs during neuronal cell death. In the present study, we showed that the neurotoxic beta-amyloid peptide A beta(25-35) caused a dose-dependent (0.1-10 mu M) and time-dependent (> 12 h) enhancement of both inactivating and non-inactivating components of voltage-de pendent K+ (VGK) currents in nerve growth factor-differentiated rat phaeochromocytoma (PC-12) cells and primary rat hippocampal neurones. Similar effects were exerted by A beta(1-42), but not by the non-neurotoxic A beta(35-25) peptide. A beta(25-35) and A beta(1-42) caused an early (15-20 min) increase in intracellular Ca2+ concentration. This led to an increased production of reactive oxygen species (ROS), which peaked at 3 h and lasted for 24 h; ROS production seemed to trigger the VGK current increase as vitamin E (50 mu M) blocked both the A beta(25-35)- and A beta(1-42)-induced ROS increase and VGK current enhancement. Inhibition of protein synthesis (cyclo-heximide, 1 mu g/mL) and transcription (actinomycin D, 50 ng/mL) blocked A beta(25-35)-induced VGK current enhancement, suggesting that this potentiation is mediated by transcriptional activation induced by ROS. Interestingly, the specific nuclear factor-kappa B inhibitor SN-50 (5 mu M), but not its inactive analogue SN-50M (5 mu M), fully counteracted A beta(1-42)- or A beta(25-35)-induced enhancement of VGK currents, providing evidence for a role of this family of transcription factors in regulating neuronal K+ channel function during exposure to A beta.
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