Voltage-dependent large-conductance Ca(2+)-activated K(+) channels, often referred to as
BK channels, are a unique class of
ion channels coupling intracellular chemical signaling to electrical signaling.
BK channel expression has been shown to be up-regulated in human
glioma biopsies, and expression levels correlate positively with the
malignancy grade of the
tumor.
Glioma BK channels (gBK) are a splice variant of the hslo gene, are characterized by enhanced sensitivity to [Ca(2+)](i), and are the target of modulation by
growth factors. By using the selective pharmacological
BK channel inhibitor
iberiotoxin, we examined the potential role of these channels in
tumor growth. Cell survival assays examined the ability of
glioma cells to grow in nominally serum-free medium. Under such conditions,
BK channel inhibition by
iberiotoxin caused a dose- and time-dependent decrease in cell number discernible as early as 72 hr after exposure and maximal growth inhibition after 4-5 days. FACS analysis shows that
IbTX treatment arrests
glioma cells in S phase of the cell cycle, whereupon cells undergo cell death. Interestingly,
IbTX effects were nullified when cells were maintained in 7%
fetal calf serum. Electrophysiological analysis, in conjunction with biotinylation studies, demonstrates that serum
starvation caused a significant translocation of
BK channel protein to the plasma membrane, corresponding to a two- to threefold increase in whole-cell conductance, but without a change in total gBK
protein. Hence, expression of functional gBK channels appears to be regulated in a
growth-factor-dependent manner, with enhanced surface expression promoting
tumor cell growth under conditions of
growth factor deprivation as might occur under in vivo conditions.