RT Journal Article
SR Electronic
T1 Voltage-Activated K+ Channels and Membrane Depolarization Regulate Accumulation of the Cyclin-Dependent Kinase Inhibitors p27Kip1 and p21CIP1 in Glial Progenitor Cells
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5380
OP 5392
DO 10.1523/JNEUROSCI.19-13-05380.1999
VO 19
IS 13
A1 Cristina A. Ghiani
A1 Xiaoqing Yuan
A1 Alex M. Eisen
A1 Peter L. Knutson
A1 Ronald A. DePinho
A1 Chris J. McBain
A1 Vittorio Gallo
YR 1999
UL http://www.jneurosci.org/content/19/13/5380.abstract
AB Neural cell development is regulated by membrane ion channel activity. We have previously demonstrated that cell membrane depolarization with veratridine or blockage of K+channels with tetraethylammonium (TEA) inhibit oligodendrocyte progenitor (OP) proliferation and differentiation (Knutson et al., 1997); however the molecular events involved are largely unknown. Here we show that forskolin (FSK) and its derivative dideoxyforskolin (DFSK) block K+ channels in OPs and inhibit cell proliferation. The antiproliferative effects of TEA, FSK, DFSK, and veratridine were attributable to OP cell cycle arrest in G1 phase. In fact, (1) cyclin D accumulation in synchronized OP cells was not affected by K+ channel blockers or veratridine; (2) these agents prevented OP cell proliferation only if present during G1 phase; and (3) G1 blockers, such as rapamycin and deferoxamine, mimicked the anti-proliferative effects of K+channel blockers. DFSK also prevented OP differentiation, whereas FSK had no effect. Blockage of K+ channels and membrane depolarization also caused accumulation of the cyclin-dependent kinase inhibitors p27Kip1 and p21CIP1 in OP cells. The antiproliferative effects of K+channel blockers and veratridine were still present in OP cells isolated from INK4a−/− mice, lacking the cyclin-dependent kinase inhibitors p16INK4a and p19ARF. Our results demonstrate that blockage of K+ channels and cell depolarization induce G1 arrest in the OP cell cycle through a mechanism that may involve p27Kip1 and p21CIP1 and further support the conclusion that OP cell cycle arrest and differentiation are two uncoupled events.