TY - JOUR T1 - Voltage-Activated K<sup>+</sup> Channels and Membrane Depolarization Regulate Accumulation of the Cyclin-Dependent Kinase Inhibitors p27<sup>Kip1</sup> and p21<sup>CIP1</sup> in Glial Progenitor Cells JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5380 LP - 5392 DO - 10.1523/JNEUROSCI.19-13-05380.1999 VL - 19 IS - 13 AU - Cristina A. Ghiani AU - Xiaoqing Yuan AU - Alex M. Eisen AU - Peter L. Knutson AU - Ronald A. DePinho AU - Chris J. McBain AU - Vittorio Gallo Y1 - 1999/07/01 UR - http://www.jneurosci.org/content/19/13/5380.abstract N2 - 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. ER -