K-PROLIFERATION ARE REGULATED BY INTRACELLULAR SODIUM AND MEMBRANE DEPOLARIZATION IN OLIGODENDROCYTE PROGENITOR CELLS( CHANNEL EXPRESSION AND CELL)

The effects of a variety of antiproliferative agents on voltage-depend ent K+ channel function in cortical oligodendrocyte progenitor (O-2A) cells were studied. Previously, we had shown that glutamate receptor a ctivation reversibly inhibited O-2A cell proliferation stimulated by m itogenic factors and prevented lineage progression by attenuating outw ard K+ currents in O-2A cells. We now show that the antiproliferative actions of glutamate receptor activation are Ca2+-independent and aris e from an increase in intracellular Nat and subsequent block of outwar d Kt currents. In support of this mechanism, agents that acted to depo larize O-2A cells or increase intracellular sodium similarly had an an tiproliferative effect, attributable at least in part to a reduction i n voltage-gated K+ currents. Also, these effects were reversible and C a2+-independent. Chronic treatment with glutamate agonists was without any long-term effect on K+ current function. Cells cultured in elevat ed K+, however, demonstrated an upregulation of inward rectifier K+ cu rrents, concomitant with an hyperpolarization of the resting membrane potential. This culture condition therefore promoted a current phenoty pe typical of pro-oligodendroblasts. Finally, cells chronically treate d with the mitotic inhibitor retinoic acid displayed a selective downr egulation 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 oligo dendrocyte lineage plays an important role in determining their prolif erative potential and demonstrate that O-2A cell K+ current phenotype can be modified by long-term depolarization of the cell membrane.