title: Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes.
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 (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.
authors.affiliation: Department of Neurobiology, University of Alabama, Birmingham, Alabama, USA. macfarlan@nrc.uab.edu
authors.forename: S N
authors.initials: SN
authors.lastname: MacFarlane
authors.forename: H
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: 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*
chemical_list: D007473:Ion Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D015222:Sodium Channels; D012964:Sodium