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Volume 272, Number 13, Issue of March 28, 1997 pp. 8346-8352
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Cellular Uptake of Lead Is Activated by Depletion of Intracellular Calcium Stores

(Received for publication, September 23, 1996, and in revised form, January 6, 1997)

From the Department of Pharmacology and Physiology and the Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

The mechanisms of cellular lead uptake were characterized using a fluorescence method in cells loaded with indo-1. Pb²⁺ bound to intracellular indo-1 with much higher affinity than Ca²⁺ and quenched fluorescence at all wavelengths. Pb²⁺ uptake into pituitary GH₃ cells, glial C₆ cells, and a subclone of HEK293 cells was assessed by fluorescence quench at a Ca²⁺-insensitive emission wavelength. Pb²⁺ uptake was concentration- and time-dependent. Pb²⁺ uptake in all three cell types occurred at a much faster rate when intracellular Ca²⁺ stores were depleted by two different methods: addition of drugs that inhibit the endoplasmic reticulum Ca²⁺ pump (thapsigargin, cyclopiazonic acid, and tert-butylhydroquinone), and prolonged incubation of cells in Ca²⁺-free media. Application of receptor agonists, which deplete intracellular Ca²⁺ stores via inositol trisphosphate-sensitive channels, did not activate Pb²⁺ uptake. Agonists were just as effective as thapsigargin in stimulating uptake of Ca²⁺ but less so in stimulating uptake of Mn²⁺. Basal and stimulated Pb²⁺ uptake were partially reduced by 1 mM extracellular Ca²⁺ and strongly inhibited by 10 mM Ca²⁺. Pb²⁺ entry in GH₃ cells was inhibited by two drugs that block capacitative Ca²⁺ entry, La³⁺ and SK&F 96365. Depolarization of electrically excitable GH₃ cells increased the initial rate of Pb²⁺ uptake 1.6-fold, whereas thapsigargin increased uptake 12-fold. In conclusion, Pb²⁺ crosses the plasma membrane of GH₃, C₆, and HEK293 cells via channels that are activated by profound depletion of intracellular Ca²⁺ stores.

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