Enhancement of outward potassium current may participate in beta-amyloid peptide-induced cortical neuronal death.
In light of recent evidence implicating the upregulation of outward K+ current in mediating several forms of neuronal apoptosis, we tested the hypothesis that such an upregulation might specifically contribute to the pathogenesis of beta-amyloid peptide (A beta)-induced neuronal death. Exposure to A beta fragment 25-35 (20 microM) or 1-42 (20 microM) enhanced the delayed rectifier K+ current IK, shifting its activation voltage relationship toward hyperpolarized levels and increasing maximal conductance, but did not affect the transient K+ current IA or charybdotoxin-sensitive BK current. Reducing IK by adding the channel blocker tetraethylammonium (TEA, 5 mM) or raising extracellular K+ to 25 mM attenuated A beta-induced neuronal death, even in the presence of nifedipine or gadolinium to block associated increases in Ca2+ influx. The IA blocker 4-aminopyridine (4-AP, 5 mM) and the CI- channel blocker anthracene-9-carboxylic acid (ACA, 500 microM) were not neuroprotective. These data raise the intriguing possibility that manipulations aimed at reducing outward K+ current may provide an approach to reducing neuronal degeneration in patients with Alzheimer's disease.
Yu
S P
SP
Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Farhangrazi
Z S
ZS
Ying
H S
HS
Yeh
C H
CH
Choi
D W
DW
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018920:Coculture Techniques; D051668:Delayed Rectifier Potassium Channels; D005333:Fetus; D051379:Mice; D009457:Neuroglia; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D051668:Delayed Rectifier Potassium Channels; D010446:Peptide Fragments; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C027917:tetramethylammonium; D011188:Potassium