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.