Cell volume in the regulation of cell proliferation and apoptotic cell death

Cell proliferation must - at some time point - lead to increase of cell vol ume and one of the hallmarks of apoptosis is cell shrinkage. At constant ex tracellular osmolarity those alterations of cell volume must reflect respec tive changes of cellular osmolarity which are hardly possible without the p articipation of cell volume regulatory mechanisms. Indeed, as shown for ras oncogene expressing 3T3 fibroblasts, cell proliferation is paralleled by a ctivation of Na+/H+ exchange and Na+,K+,2Cl(-) cotransport, the major trans port systems accomplishing regulatory cell volume increase. Conversely, as evident from CD95-induced apoptotic cell death, apoptosis is paralleled by inhibition of Na+/H+ exchanger and by activation of Cl- channels and releas e of the organic osmolyte taurine, major components of regulatory cell volu me decrease. However, ms oncogene activation leads to activation and CD95 r eceptor triggering to inhibition of K+ channels. The effects counteract the respective cell volume changes. Presumably, they serve to regulate cell me mbrane potential, which is decisive for Ca++ entry through I-CRAC and the g eneration of cytosolic Ca++ oscillations in proliferating cells. As a matte r of fact I-CRAC is activated in ras oncogene expressing cells and inhibite d in CD95-triggered cells. Activation of K+ channels and Na+/H+ exchanger a s well as Ca++ oscillations have been observed in a wide variety of cells u pon exposure to diverse mitogenic factors. Conversely, diverse apoptotic fa ctors have been shown to activate Cl- channels and organic osmolyte release . Inhibition of K+ channels is apparently, however, not a constant phenomen on paralleling apoptosis which in some cells may even require the operation of K+ channels. Moreover, cell proliferation may at some point require act ivation of Cl- channels. In any case, the alterations of cell volume are ob viously important for the outcome, as cell shrinkage impedes cell prolifera tion and apoptosis can be elicited by increase of extracellular osmolarity. At this stage little is known about the interplay of cell volume regulator y mechanisms and the cellular machinery leading to mitosis or death of the cell. Thus, considerable further experimental effort is required in this ex citing area of cell physiology. Copyright (C) 2000 S. Karger AG Basel.