Ion channels and cell volume in regulation of cell proliferation and apoptotic cell death.

Cell proliferation must be accompanied by increase of cell volume and apoptosis is typically paralleled by cell shrinkage. Moreover, profound osmotic cell shrinkage may trigger apoptosis. In isotonic environment cell volume changes require the respective alterations of transport across the cell membrane. Cell proliferation is typically paralleled by activation of K(+) channels, which is required for the maintenance of the cell membrane potential, a critical determinant of Ca(2+) entry through Ca(2+) channels. The Ca(2+) entry leads to oscillations of cytosolic Ca(2+) activity which is followed by activation of Ca(2+) dependent transcription factors and by depolymerization of the actin filament network. The latter disinhibits the Na(+) H(+) exchanger and Na(+) , K(+) , 2Cl(-)cotransport thus leading to cell swelling. At some point transient activation of Cl(-) channels is required leading to transient decrease of cell volume. Apoptosis is typically paralleled by sustained activation of Cl(-) channels leading to Cl(-) , HCO-(3) and osmolyte exit. The subsequent cell shrinkage and cytosolic acidification are not counter-regulated by activation of the Na(+) /H(+) exchanger, which is inhibited and eventually degraded during apoptosis. At a later stage K(+) exit through K(+) channels decreases intracellular K(+) concentration and facilitates cell shrinkage. Sustained or excessive increase of Ca(+) triggers apoptotic cell death, typically paralleled by cell shrinkage due to activation of Ca(2+) sensitive K(+) channels. Cellular K(+) loss and cell shrinkage are supportive but not required for the induction of apoptosis. On the other hand, several studies point to a critical role of K(+) -channel inhibition in the initiation of apoptosis. Thus, alterations of K(+) channel and Ca(2+) channel activities may participate in the triggering of both, cell proliferation and apoptosis. The impact of those channels depends on magnitude and temporal organization of channel activation and on the activity of further signaling mechanisms. Accordingly, the same ion channel blockers may interfere with both, cell proliferation and apoptosis depending on cell type, regulatory environment and condition of the cell.