Chronic Li + attenuates agonist- and phorbol ester-mediated Na +/H + antiporter activity in HL-60 cells

Abstract

The effects of Li + on signal transduction in dibutyrl cAMP-differentiated HL-60- cells were studied. Upon differentiation, these human promyelocytic leukemia cells express a chemotactic formyl peptide receptor, which is coupled through a guanine nucleotide-binding protein to phospholipase C. Stimulation with fMet-Leu-Phe results in changes in intracellular pH which are thought to be mediated by protein kinase C regulation of Na −/H + antiporter function. Acute LiCl treatment (10 mM) was without any effect on Na +/H + activity. However, pretreatment of HL-60 cells with 1 or 10 mM LiCl for at least 5 days resulted in a marked attenuation of fMet-Leu-Phe effects on Na +/H + activity. In undifferentiated HL-60 cells, which lack fMet-Leu-Phe receptors, intracellular acidification induced by the proton ionophore nigericin generates an alkalinization response. Chronic (but not acute) Li + treatment also resulted in an inhibition of nigericin-mediated response. Furthermore, stimulation of the Na +/H + antiporter by the phorbol ester, phorbol-12-myristate-13-acetate, was also markedly attenuated by chronic LiCl treatment, suggesting an impairment of protein kinase C activity. In contrast, fMet-Leu-Phe-induced increases in intracellular Ca 2+ and phospho-inositide breakdown were unchanged in cells treated with Li + for 5 days. These results indicate that chronic but not acute Li + treatment alters intracellular pH regulation possibly at a site distal to the fMet-Leu-Phe receptor.