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Links between cell proliferation and K channel activity

M.L. Day, Department of Physiology, University of Sydney, NSW 2006, Australia.

Changes in the activity of potassium channels are required for proliferation of a wide variety of cell types. Pharmacological inhibition of K+ channel activity can cause cell cycle arrest. Our studies on the regulation of ion channels during pre-implantation development of the mouse embryo have provided some insight into the mechanisms linking channel activity to the cell cycle. Using the patch-clamp technique, we have shown that the activity of a large-conductance K+ channel in the early mouse embryo is regulated by the cell cycle (Day et al., 1993). This K+ channel is active during M and G1 phases and inactive during S and G2 phases. In parallel with the changes in K+ channel activity there are changes in cell membrane potential such that the membrane potential is hyperpolarised when the channel is active.

The activation of this K+ channel at the G2/M transition of early embryonic cell cycles does not depend on the activation of the mitotic kinase, Cdk1, and does not require the presence of the nucleus (Day et al., 1998a). Thus it appears that a cytoplasmic cell cycle is functional in the early mouse embryo to regulate K+ channel activity. This cytoplasmic clock is, however, not completely uninfluenced by the nuclear cell cycle clock since inactivation of the channel as the cell cycle exits M phase is affected by Cyclin B/Cdk1 activity, and inhibition of DNA synthesis prevents the decrease in channel activity that normally occurs at the G1-S transition. Thus, the K+ channel in the early mouse embryo is controlled both by nuclear and cytoplasmic clocks.

Several roles for K+ channels in cell proliferation have been proposed. For example, a change in K+ channel activity can cause a change in cell membrane potential that can then alter the activity of other voltage-gated ion channels, such as Ca2+ channels. In the case of the K+ channel in the embryo, this role is possible since we have observed not only parallel variations in membrane potential but also cell cycle-dependent changes in the amplitude of a T-type Ca2+ current (Day et al., 1998b). A second, possible role for the K+ channel in the embryo is in cell volume homeostasis. There is some evidence for this possibility since a cell swelling-induced Cl current is regulated by the cell cycle in mouse embryos being inactive during metaphase of mitosis in the 2-cell embryo at a time when the K+ channel is also active (Kolajova et al., 2001).

Day, M.L., Pickering, S.J., Johnson, M.H. & Cook, D.I. (1993) Nature, 365: 560-562.

Day, M.L., Johnson, M.H. & Cook D.I. (1998a) EMBO Journal, 17: 1952-1960.

Day, M.L., Johnson, M.H. & Cook D.I. (1998b) Pflügers Archiv European Journal of Physiology, 436: 834-842.

Kolajova, M., Hammer, M., Collins, J. & Baltz, J. (2001) Development, 128: 3427-3434.