Nuclear factor‐κB activation by reactive oxygen species mediates voltage‐gated K + current enhancement by neurotoxic β‐amyloid peptides in nerve growth factor‐differentiated PC‐12 cells and hippocampal neurones

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 β‐amyloid peptide Aβ 25−35 caused a dose‐dependent (0.1–10 µ m ) and time‐dependent (> 12 h) enhancement of both inactivating and non‐inactivating components of voltage‐dependent K + (VGK) currents in nerve growth factor‐differentiated rat phaeochromocytoma (PC‐12) cells and primary rat hippocampal neurones. Similar effects were exerted by Aβ 1−42 , but not by the non‐neurotoxic Aβ 35−25 peptide. Aβ 25−35 and Aβ 1−42 caused an early (15–20 min) increase in intracellular Ca 2+ 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 µ m ) blocked both the Aβ 25−35 ‐ and Aβ 1−42 ‐induced ROS increase and VGK current enhancement. Inhibition of protein synthesis (cycloheximide, 1 µg/mL) and transcription (actinomycin D, 50 ng/mL) blocked Aβ 25−35 ‐induced VGK current enhancement, suggesting that this potentiation is mediated by transcriptional activation induced by ROS. Interestingly, the specific nuclear factor‐κB inhibitor SN‐50 (5 µ m ), but not its inactive analogue SN‐50M (5 µ m ), fully counteracted Aβ 1−42 ‐ or Aβ 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 Aβ.