The role of ion transport in the regulation of cell proliferation.

The stimulation of growth in a variety of cell types is followed by rapid changes in ion transport across the plasma membrane and in the intracellular concentration of various ions. The addition of various growth factors to fibroblasts, for example, causes stimulation of Na+ entry through the Na(+)-H+ antiport. This results in the alkalinization of the cytosol and an increase in intracellular Na+ concentration. The increased intracellular Na+ in turn stimulates the Na+/K+ pump, raising the concentration of K+ and lowering the Na+ toward normal. These changes in monovalent ion transport appear to be a necessary part of the proliferative response. In addition to the changes in cytosolic Na+, K+, and pH, a number of growth factors also cause a rapid increase in the cytosolic concentration of Ca2+. The additional Ca2+ appears to come from intracellular organelles, since the effect does not require Ca2+ in the extracellular medium. The change in intracellular Ca2+ concentration persists for only a few minutes. Changes in ion transport have been observed after the addition of mitogens to a variety of cell types, including epithelial cells. For example, we have found that stimulation of proliferation of MDCK (dog kidney epithelial) cells by either serum or vasopressin is followed by stimulation of the activity of the Na+/K+ pump. The manner in which these rapid changes in ion transport may play a role in signalling the onset of the mitogenic response will be discussed.