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Role of the Outward Delayed Rectifier K + Current in Ceramide‐Induced Caspase Activation and Apoptosis in Cultured Cortical Neurons
Author(s) -
Yu Shan Ping,
Yeh ChenHsiung,
Gottron Frank,
Wang Xin,
Grabb Margaret C.,
Choi Dennis W.
Publication year - 1999
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.1471-4159.1999.0730933.x
Subject(s) - ceramide , apoptosis , microbiology and biotechnology , tyrosine phosphorylation , lipid signaling , tetraethylammonium , tyrosine kinase , biology , programmed cell death , chemistry , sphingomyelin , kinase , signal transduction , biochemistry , receptor , potassium , organic chemistry , membrane
: We studied the novel hypothesis that an upmodulation of channels for outward delayed rectifier K + current ( I κ ) plays a key role in ceramide‐induced neuronal apoptosis. Exposure for 6‐10 h to the membrane‐permeable C 2 ‐ceramide (25 μ M ) or to sphingomyelinase (0.2 unit/ml), but not to the inactive ceramide analogue C 2 ‐dihydroceramide (25 μ M ), enhanced the whole‐cell I κ current without affecting the transient A‐type K + current and increased caspase activity, followed by neuronal apoptosis 24 h after exposure onset. Tetraethylammonium (TEA) or 4‐chloro‐ N,N ‐diethyl‐ N ‐heptylbenzenebutanaminium tosylate (clofilium), at concentrations inhibiting I κ , attenuated the C 2 ‐ceramide‐induced caspase‐3‐like activation as well as neuronal apoptosis. Raising extracellular K + to 25 m M similarly blocked the C 2 ‐ceramide‐induced cell death ; the neuroprotection by 25 m M K + or TEA was not eliminated by blocking voltage‐gated Ca 2+ channels. An inhibitor of tyrosine kinases, herbimycin A (10 n M ) or lavendustin A (0.1‐1 μ M ), suppressed I κ enhancement and/or apoptosis induced by C 2 ‐ceramide. It is suggested that ceramide‐induced I κ current enhancement is mediated by tyrosine phosphorylation and plays a critical role in neuronal apoptosis.