BICARBONATE RAISES pH VIA NaHC03/HC1 EXCHANGE AND ATTENUATES THE ACTIVATION OF Na+/H' EXCHANGE BY SERUM*

There is abundant evidence implicating a role for intracellular pH (pHin) in the proliferative response of many cells to mitogenic agents. In mammalian cells, pHin is generally regulated by two systems: Na+/H+ exchange and HCO; transport. Activation of Na+/H+ exchange is one of the earliest responses of mammalian cells to mitogens. In the absence of HCO;, this activation raises the pHin. However, in the presence of HCO;, the effect of mitogens on the pHin is unclear. HCO; regulates pHi, via mechanisms which can either acidify or alkalinize the cytosol, depending on the cell type and tissue of origin. BALB/c 3T3 mouse embryo cells are employed in the present study because they are used extensively in investigations of mammalian cell proliferation. Since these cells are of indefinite origin, there is no way to predict which HCO; transporting system is operable in these cells and, hence, what effect HCO; will have on the pHin and the response of pHi, to mitogens. In the present article, we examine the mechanism and effect of HC0;-based pHin regulation. Our results indicate that HCOi-dependent pHin regulation in BALB/c 3T3 cells occurs via NaHCO,/HCl exchange which raises pHin under physiological conditions. This activity can raise the pHin to above the set point of the activated Na+/H+ exchanger, consequently attenuating the mitogen-induced Na+/H+ exchange-mediated increases in pHi,.