title: Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals.
abstract: Amyloid beta protein (A beta), the central constituent of senile plaques in Alzheimer's disease (AD) brain, is known to exert toxic effects on cultured neurons. The role of the voltage-sensitive Ca2+ channel (VSCC) in beta (25-35) neurotoxicity was examined using rat cultured cortical and hippocampal neurons. When L-type VSCCs were blocked by application of nimodipine, beta (25-35) neurotoxicity was attenuated, whereas application of omega-conotoxin GVIA (omega-CgTX-GVIA) or omega-agatoxin IVA (omega-Aga-IVA), the blocker for N- or P/Q-type VSCCs, had no effects. Whole-cell patch-clamp studies indicated that the Ca2+ current density of beta (25-35)-treated neurons is about twofold higher than that of control neurons. Also, beta (25-35) increased Ca2+ uptake, which was sensitive to nimodipine. The 2', 7'-dichlorofluorescin diacetate assay showed the ability of beta (25-35) to produce reactive oxygen species. Nimodipine had no effect on the level of free radicals. In contrast, vitamin E, a radical scavenger, reduced the level of free radicals, neurotoxicity, and Ca2+ uptake. These results suggest that beta (25-35) generates free radicals, which in turn, increase Ca2+ influx via the L-type VSCC, thereby inducing neurotoxicity.
authors.affiliation: CNS Research Laboratories, Shionogi and Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ueda
authors.forename: S
authors.initials: S
authors.lastname: Shinohara
authors.forename: T
authors.initials: T
authors.lastname: Yagami
authors.forename: K
authors.initials: K
authors.lastname: Asakura
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004553:Electric Conductivity; D004594:Electrophysiology; D005609:Free Radicals; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats / Q000196:embryology
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D005609:Free Radicals; D009498:Neurotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D009553:Nimodipine; D002118:Calcium