K+ channel expression and cell proliferation are regulated by intracellular sodium and membrane depolarization in oligodendrocyte progenitor cells.
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.
Knutson
P
P
Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495, USA.
Ghiani
C A
CA
Zhou
J M
JM
Gallo
V
V
McBain
C J
CJ
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology*; D004622:Embryo, Mammalian; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000096:biosynthesis*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation; D014701:Veratridine / Q000494:pharmacology
D010982:Platelet-Derived Growth Factor; D015221:Potassium Channels; D011810:Quinoxalines; D016222:Fibroblast Growth Factor 2; D000001:Calcimycin; D014212:Tretinoin; C056723:FG 9041; D014701:Veratridine; D012964:Sodium; D011188:Potassium; D007608:Kainic Acid; D002118:Calcium