Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes

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Abstract
Arrest of spinal cord astrocytes at defined stages of the cell cycle clock causes significant changes in the expression of voltage‐activated Na+ and K+ currents. Arrest of actively proliferating astrocytes in G1/G0 by all‐trans‐retinoic acid induces premature expression of inwardly rectifying K+ currents (IKIR) typically expressed only in differentiated astrocytes. By contrast, arrest in S phase by ara‐C or Aphidicolin leads to a greater than twofold increase in “delayed” outwardly rectifying currents (IKD) and a concomitant decrease in IKIR. Pharmacological blockade of IKD by TEA and 4AP caused proliferating astrocytes to arrest in G0/G1, suggesting that activity of these channels is required for G1/S checkpoint progression. Conversely, in quiescent astrocytes, inhibition of IKIR by 30 μM BaCl2 led to an increase in astrocyte proliferation and to an increase in the number of cells in S phase from 5% to 26%. These data suggest that a downregulation of KIR promotes cell cycle progression through the G1/S checkpoint. Blockade of IKIR in actively proliferating cells, however, leads to an accumulation in G2/M, suggesting that reappearance of this current may be critical for progression beyond DNA synthesis. Interestingly, Na+ currents (INa+) are increased greater than fourfold in S phase‐arrested cells, yet their pharmacological blockade by TTX has no effect on cell cycle progression. However, the resting membrane potential of S phase‐arrested cells increases profoundly, and manipulation of membrane potential by the application of low concentrations of ouabain, or reduction of extracellular potassium, induces the accumulation of quiescent astrocytes in S phase of the cell cycle, suggesting that either depolarization or intracellular sodium, or both, play an important role in promoting astrocyte proliferation. GLIA 30:39–48, 2000.