Sp. Yu et al., Role of the outward delayed rectifier K+ current in ceramide-induced caspase activation and apoptosis in cultured cortical neurons, J NEUROCHEM, 73(3), 1999, pp. 933-941
We studied the novel hypothesis that an up-modulation of channels for outwa
rd delayed rectifier K+ current (I-K) plays a key role in ceramide-induced
neuronal apoptosis. Exposure for 6-10 h to the membrane-permeable C-2-ceram
ide (25 mu M) or to sphingomyelinase (0.2 unit/ml), but not to the inactive
ceramide analogue C-2-dihydroceramide (25 mu M), enhanced the whole-cell I
-K 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-heptylbenzenebutanamini
um tosylate (clofilium), at concentrations inhibiting I-K, attenuated the C
-2-ceramide-induced caspase-3-like activation as well as neuronal apoptosis
. Raising extracellular K+ to 25 mM similarly blocked the C-2-ceramide-indu
ced cell death; the neuroprotection by 25 mM K+ or TEA was not eliminated b
y blocking voltage-gated Ca2+ channels. An inhibitor of tyrosine kinases, h
erbimycin A (10 nM) or lavendustin A (0.1-1 mu M), suppressed I-K enhanceme
nt and/or apoptosis induced by C-2-ceramide. It is suggested that ceramide-
induced I-K current enhancement is mediated by tyrosine phosphorylation and
plays a critical role in neuronal apoptosis.