Nuclear factor-kappaB activation by reactive oxygen species mediates voltage-gated K+ current enhancement by neurotoxic beta-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 beta-amyloid peptide Abeta(25-35) caused a dose-dependent (0.1-10 microm) 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 Abeta(1-42), but not by the non-neurotoxic Abeta(35-25) peptide. Abeta(25-35) and Abeta(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 microm) blocked both the Abeta(25-35)- and Abeta(1-42)-induced ROS increase and VGK current enhancement. Inhibition of protein synthesis (cycloheximide, 1 microg/mL) and transcription (actinomycin D, 50 ng/mL) blocked Abeta(25-35)-induced VGK current enhancement, suggesting that this potentiation is mediated by transcriptional activation induced by ROS. Interestingly, the specific nuclear factor-kappaB inhibitor SN-50 (5 microm), but not its inactive analogue SN-50M (5 microm), fully counteracted Abeta(1-42)- or Abeta(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 Abeta.