Characterization of the activation of Na+/H+ exchange in lymphocytes by phorbol esters: change in cytoplasmic pH dependence of the antiport.

Phorbol 12-myristate 13-acetate and other phorbol esters induce an intracellular alkalinization in rat thymic lymphocytes. An extracellular acidification can be recorded concomitantly. This transmembrane H+ (equivalent) flux is dependent on external Na+ and is amiloride sensitive. Phorbol esters also stimulate an amiloride-sensitive uptake of 22Na+, suggesting activation of Na+o/H+i exchange. Only those phorbol derivatives that are tumor promoters and activators of protein kinase C stimulate the antiport. Activation of the Na+/H+ exchange is brought about by a change in the cytoplasmic pH sensitivity of the antiport. Activation of the Na+/H+ exchanger by phorbol esters results in membrane hyperpolarization, due to indirect stimulation of the electrogenic Na+/K+ pump by the increased intracellular Na+ concentration. Increased Na+/H+ exchange also produces cell swelling, which may be one of the earliest manifestations of the growth-promoting properties of the phorbol esters.