Beta-amyloid peptide blocks the fast-inactivating K+ current in rat hippocampal neurons.
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.
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Department of Chemical Engineering, University of Wisconsin, Madison 53706, USA.
Smith
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Murphy
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D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D004553:Electric Conductivity; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008564:Membrane Potentials; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C078592:amyloid beta-protein (1-40); D002118:Calcium