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The Journal of Neuroscience, July 1, 1999, 19(13):5380-5392

Voltage-Activated K⁺ Channels and Membrane Depolarization Regulate Accumulation of the Cyclin-Dependent Kinase Inhibitors p27^Kip1 and p21^CIP1 in Glial Progenitor Cells

Cristina A. Ghiani¹, Xiaoqing Yuan¹, Alex M. Eisen¹, Peter L. Knutson¹, Ronald A. DePinho², Chris J. McBain¹, and Vittorio Gallo¹

¹ Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495, and ² Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

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 p27^Kip1 and p21^CIP1 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 p16^INK4a and p19^ARF. 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 p27^Kip1 and p21^CIP1 and further support the conclusion that OP cell cycle arrest and differentiation are two uncoupled events.

Key words: oligodendrocyte development; cell cycle; ion channels; G1 arrest; cell proliferation; cyclin D

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19135380-13$05.00/0

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