K+Channel Expression and Cell Proliferation Are Regulated by Intracellular Sodium and Membrane Depolarization in Oligodendrocyte Progenitor Cells

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Abstract
The effects of a variety of antiproliferative agents on voltage-dependent K+channel function in cortical oligodendrocyte progenitor (O-2A) cells were studied. Previously, we had shown that glutamate receptor activation reversibly inhibited O-2A cell proliferation stimulated by mitogenic factors and prevented lineage progression by attenuating outward K+currents in O-2A cells. We now show that the antiproliferative actions of glutamate receptor activation are Ca2+-independent and arise from an increase in intracellular Na+and subsequent block of outward K+currents. In support of this mechanism, agents that acted to depolarize O-2A cells or increase intracellular sodium similarly had an antiproliferative effect, attributable at least in part to a reduction in voltage-gated K+currents. Also, these effects were reversible and Ca2+-independent. Chronic treatment with glutamate agonists was without any long-term effect on K+current function. Cells cultured in elevated K+, however, demonstrated an upregulation of inward rectifier K+currents, concomitant with an hyperpolarization of the resting membrane potential. This culture condition therefore promoted a current phenotype typical of pro-oligodendroblasts. Finally, cells chronically treated with the mitotic inhibitor retinoic acid displayed a selective downregulation of outward K+currents. In conclusion, signals that affect O-2A cell proliferation do so by regulating K+channel function. These data indicate that the regulation of K+currents in cells of the oligodendrocyte lineage plays an important role in determining their proliferative potential and demonstrate that O-2A cell K+current phenotype can be modified by long-term depolarization of the cell membrane.