Cytoplasmic pH and Free Ca2+ in the Action of Growth Factors

Among the immediate consequences of growth factor-receptor interaction are the activation of various ion transport systems in the plasma membrane and changes in intracellular ionic composition. Mitogen-induced alterations in the levels of cytoplasmic free Ca2+ ([Ca2+]i) and H+ are of special interest, because these ions are thought to serve as second messengers that trigger and regulate cell proliferation. During the past few years our understanding of the ionic changes in growth factor-stimulated cells has increased dramatically. In particular, the molecular mechanisms responsible for a transient rise in [Ca2+]i and for a sustained increase in cytoplasmic pH (pHi) have been largely unraveled, and much effort is now being devoted to determining how these ionic signals might contribute to a proliferative response. This review describes the Ca2+ and pH signals generated by growth factor receptors, with emphasis on the activation of Na+ /H+ exchange and the resultant rise in pHi, which has a permissive effect on the initiation of DNA synthesis in mitogenstimulated cells.