Phorbol ester and diacylglycerol mimic growth factors in raising cytoplasmic pH

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Abstract
There is now good evidence that cytoplasmic pH (pHi) may have an important role in the metabolic activation of quiescent cells. In particular, growth stimulation of mammalian fibroblasts leads to a rapid increase in pHi, due to activation of a Na+/H+ exchanger in the plasma membrane and this alkalinization is necessary for the initiation of DNA synthesis. The mechanism by which mitogens activate the Na+/H+ exchanger to raise pHi is not known, although an increase in cytoplasmic free Ca2+ ([Ca2+]i) was postulated as the primary trigger. The Na+/H+ exchanger evidently is set in motion through protein kinase C, a phospholipid- and Ca2+-dependent enzyme normally activated by diacylglycerol produced from inositol phospholipids in response to external stimuli. Using newly developed pH microelectrodes and fluorimeric techniques, it was shown that a tumor promoting phorbol ester and synthetic diacylglycerol, both potent activators of kinase C, mimic the action of mitogens in rapidly elevating pHi in different cell types. Contrary to previous views, an early rise in [Ca2+]i is not essential for the activation of Na+/H+ exchange and the resultant increase in pHi. An alkaline pHi shift, mediated by Na+/H+ exchange, may be a common signal in the action of those hormones which elicit the breakdown of inositol phospholipids. [Human foreskin fibroblasts (HF cells), HeLa cells and mouse N1E-115 neuroblastoma cells were used in this study.].