Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes.
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 (IK(IR)) 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 (IK(D)) and a concomitant decrease in IK(IR). Pharmacological blockade of IK(D) 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 IK(IR) by 30 microM BaCl(2) 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 K(IR) promotes cell cycle progression through the G1/S checkpoint. Blockade of IK(IR) 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.
MacFarlane
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Department of Neurobiology, University of Alabama, Birmingham, Alabama, USA. macfarlan@nrc.uab.edu
Sontheimer
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D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004594:Electrophysiology; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology* / Q000378:metabolism*
D007473:Ion Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015222:Sodium Channels; D012964:Sodium