Enhancement of Outward Potassium Current May Participate in B-Amyloid Peptide-Induced Cortical Neuronal Death
Dennis W. Choi, Shan P. Yu
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Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO, 63110, USA
We found that serum deprivation- or staurosporine-induced apoptosis of neocortical neurons was associated with an early enhancement of delayed rectifier (IK) current, and loss of total intracellular K+. Attenuating outward K+ current with tetraethylammonium or elevated extracellular K+ attenuated this neuronal apoptosis, even if associated increases in [Ca2+]i were prevented. Furthermore, exposure to the K+ ionophore, valinomycin, or the K+ channel opener, cromakalim, was sufficient to induce apoptosis (Science 278:114-117, 1997).
We now report that b-amyloid peptide (Ass)-induced neuronal apoptosis may also involve an enhancement of IK. Cultured murine cortical neurons exposed to Ab fragments 25-35 or 1-42 (20 M) exhibited an enhancement of the delayed rectifier K+ current IK, with a shift of its activation voltage relationship towards hyperpolarized levels and an increase in maximal conductance, without a change in the transient K+ current IA or the charybdotoxin-sensitive BK current. Reducing IK by adding the channel blocker tetraethylammonium (5 mM) or raising extracellular K+ to 25 mM, attenuated Ab-induced neuronal death, even in the presence of nifedipine or gadolinium to block associated increases in [Ca2+]i. These data raise the novel consideration that manipulations aimed at reducing outward K+ current might be useful in reducing neuronal degeneration in patients with Alzheimer's disease.