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.
Pannaccione
Anna
A
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy.
Secondo
Agnese
A
Scorziello
Antonella
A
Calì
Gaetano
G
Taglialatela
Maurizio
M
Annunziato
Lucio
L
D015761:4-Aminopyridine / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018999:Charybdotoxin / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003064:Cnidarian Venoms; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019922:GAP-43 Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016328:NF-kappa B / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D014801:Vitamin A / Q000494:pharmacology
D016229:Amyloid beta-Peptides; C059796:BDS-I antiviral protein, Anemonia sulcata; D002614:Chelating Agents; D003064:Cnidarian Venoms; D004791:Enzyme Inhibitors; D019922:GAP-43 Protein; D016328:NF-kappa B; D010446:Peptide Fragments; D010455:Peptides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; C118258:SN50 peptide; D014801:Vitamin A; D018999:Charybdotoxin; D003609:Dactinomycin; D004533:Egtazic Acid; D019789:Tetraethylammonium; D020932:Nerve Growth Factor; D015761:4-Aminopyridine; D002118:Calcium