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Amyloid β Protein Potentiates Ca 2+ Influx Through L‐Type Voltage‐Sensitive Ca 2+ Channels: A Possible Involvement of Free Radicals
Author(s) -
Ueda Keiichi,
Shinohara Shunji,
Yagami Tatsurou,
Asakura Kenji,
Kawasaki Kazuo
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.68010265.x
Subject(s) - neurotoxicity , nimodipine , chemistry , voltage dependent calcium channel , free radical scavenger , radical , reactive oxygen species , patch clamp , biophysics , biochemistry , pharmacology , calcium , antioxidant , biology , toxicity , receptor , organic chemistry
Amyloid β protein (Aβ), 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 Ca 2+ channel (VSCC) in β(25–35) neurotoxicity was examined using rat cultured cortical and hippocampal neurons. When L‐type VSCCs were blocked by application of nimodipine, β(25–35) neurotoxicity was attenuated, whereas application of ω‐conotoxin GVIA (ω‐CgTX‐GVIA) or ω‐agatoxin IVA (ω‐Aga‐IVA), the blocker for N‐ or P/Q‐type VSCCs, had no effects. Whole‐cell patch‐clamp studies indicated that the Ca 2+ current density of β(25–35)‐treated neurons is about twofold higher than that of control neurons. Also, β(25–35) increased Ca 2+ uptake, which was sensitive to nimodipine. The 2′,7′‐dichlorofluorescin diacetate assay showed the ability of β(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 Ca 2+ uptake. These results suggest that β(25–35) generates free radicals, which in turn, increase Ca 2+ influx via the L‐type VSCC, thereby inducing neurotoxicity.