L. Wang et al., Protection from cell death by mcl-1 is mediated by membrane hyperpolarization induced by K+ channel activation, J MEMBR BIO, 172(2), 1999, pp. 113-120
Mcl-1, a member of the Bcl-2 family, has been identified as an inhibitor of
apoptosis induced by anticancer agents and radiation in myeloblastic leuke
mia cells. The molecular mechanism underlying this phenomenon, however, is
not yet understood. In the present study, we report that hyperpolarization
of the membrane potential is required for prevention of mcl-1 mediated cell
death in murine myeloblastic FDC-P1 cells. In cells transfected with mcl-1
, the membrane potential, measured by the whole-cell patch clamp, was hyper
polarized more than -30 mV compared with control cells. The membrane potent
ial was repolarized by increased extracellular K+ concentration (56 mV per
10-fold change in K+ concentration). Using the cell-attached patch-clamp te
chnique, K+ channel activity was 1.7 times higher in mcl-1 transfected cell
s (NPo = 22.7 +/- 3.3%) than control cells (NPo = 13.2 +/- 1.9%). Viabiliti
es of control and mcl-1 transfected cells after treatment with the cytotoxi
n etoposide (20 mu g/ml), were 37.9 +/- 3.9% and 78.2 +/- 2.0%, respectivel
y. Suppression of K+ channel activity by 4-aminopyridine (4-AP) before etop
oside treatment significantly reduced the viability of mcl-1 transfected ce
lls to 49.0 +/- 3.6%. These results indicate that as part of the prevention
of cell death, mcl-1 causes a hyperpolarization of membrane potential thro
ugh activation of K+ channel activity.