Chronic Li+ attenuates agonist- and phorbol ester-mediated Na+/H+ antiporter activity in HL-60 cells.
The effects of Li+ on signal transduction in dibutyryl 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 the 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 Ca2+ 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.
Bitran
J A
JA
Clinical Pharmacology Section, Laboratory of Clinical Science, NIMH, National Institutes of Health, Bethesda, MD 20892.
Potter
W Z
WZ
Manji
H K
HK
Gusovsky
F
F
D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D006859:Hydrogen / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D002352:Carrier Proteins; D007295:Inositol Phosphates; D010703:Phorbol Esters; D017923:Sodium-Hydrogen Exchangers; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006859:Hydrogen; D008094:Lithium; D012964:Sodium; D002118:Calcium