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Induction of Neuronal Apoptosis by Thiol Oxidation
Author(s) -
Aizenman Elias,
Stout Amy K.,
Hartnett Karen A.,
Dineley Kirk E.,
McLaughlin BethAnn,
Reynolds Ian J.
Publication year - 2000
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.1471-4159.2000.0751878.x
Subject(s) - intracellular , programmed cell death , apoptosis , ryanodine receptor , extracellular , chemistry , calcium in biology , dna laddering , nmda receptor , microbiology and biotechnology , biochemistry , biophysics , receptor , biology , dna fragmentation
The membrane‐permeant oxidizing agent 2,2′‐dithiodipyridine (DTDP) can induce Zn 2+ release from metalloproteins in cell‐free systems. Here, we report that brief exposure to DTDP triggers apoptotic cell death in cultured neurons, detected by the presence of both DNA laddering and asymmetric chromatin formation. Neuronal death was blocked by increased extracellular potassium levels, by tetraethylammonium, and by the broad‐spectrum cysteine protease inhibitor butoxy‐carbonyl‐aspartate‐fluoromethylketone. N,N,N′,N′ ‐Tetrakis‐(2‐pyridylmethyl)ethylenediamine (TPEN) and other cell‐permeant metal chelators also effectively blocked DTDP‐induced toxicity in neurons. Cell death, however, was not abolished by the NMDA receptor blocker MK‐801, by the intracellular calcium release antagonist dantrolene, or by high concentrations of ryanodine. DTDP generated increases in fluorescence signals in cultured neurons loaded with the zinc‐selective dye Newport Green. The fluorescence signals following DTDP treatment also increased in fura‐2‐ and magfura‐2‐loaded neurons. These responses were completely reversed by TPEN, consistent with a DTDP‐mediated increase in intracellular free Zn 2+ concentrations. Our studies suggest that under conditions of oxidative stress, Zn 2+ released from intracellular stores may contribute to the initiation of neuronal apoptosis.