Beta-amyloid peptide blocks the fast-inactivating K+ current in rat hippocampal neurons

• Published in: Biophysical journal Vol. 70; no. 1; pp. 296 - 304
• Main Authors: Good, T.A., Smith, D.O., Murphy, R.M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 1996
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Biophysical Phenomena; Biophysics; Calcium - metabolism; Electric Conductivity; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Ion Channel Gating; Ion Transport - drug effects; Kinetics; Membrane Potentials; Models, Neurological; Neurons - drug effects; Neurons - metabolism; Peptide Fragments - pharmacology; Potassium Channel Blockers; Potassium Channels - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(96)79570-X

Deposition of beta-amyloid peptide (A beta) in senile plaques is a hallmark of Alzheimer disease neuropathology. Chronic exposure of neuronal cultures to synthetic A beta is directly toxic, or enhances neuronal susceptibility to excitotoxins. Exposure to A beta may cause a loss of cellular calcium homeostasis, but the mechanism by which this occurs is uncertain. In this work, the acute response of rat hippocampal neurons to applications of synthetic A beta was measured using whole-cell voltage-clamp techniques. Pulse application of A beta caused a reversible voltage-dependent decrease in membrane conductance. A beta selectively blocked the voltage-gated fast-inactivating K+ current, with an estimated KI < 10 microM. A beta also blocked the delayed rectifying current, but only at the highest concentration tested. The response was independent of aggregation state or peptide length. The dynamic response of the fast-inactivating current to a voltage jump was consistent with a model whereby A beta binds reversibly to closed channels and prevents their opening. Blockage of fast-inactivating K+ channels by A beta could lead to prolonged cell depolarization, thereby increasing Ca2+ influx.