Reversible desensitization of fibroblasts to cadmium receptor stimuli: evidence that growth in high zinc represses a xenobiotic receptor.
The xenobiotic Cd2+ triggers the production of inositol trisphosphate and releases stored Ca2+ in certain cell types, apparently by binding to a zinc site in the external domain of an "orphan" receptor (no known endogenous stimulus). Cd2+ and bradykinin evoke similar spikes in cytosolic free Ca2+. Growth in high Zn2+ (100-200 microM) abolished the free Ca2+ spike evoked by Cd2+ without affecting the spike produced by bradykinin. Growth in high Zn2+ almost abolished Cd(2+)-evoked production of [3H]inositol mono-, bis-, and trisphosphate. Bradykinin-evoked [3H]inositol phosphate production was not affected by growth in high Zn2+. Growth in high Zn2+ nearly prevented the stimulation of 45Ca2+ efflux by Cd2+ without affecting the stimulation of 45Ca2+ efflux by bradykinin or histamine. Removing Zn2+ from the culture medium and incubating the cells for several hours fully restored responsiveness to Cd2+. Cycloheximide, actinomycin D, or tunicamycin prevented the restoration of Cd2+ responsiveness, indicating that resensitization requires macromolecular synthesis. Growth in high Zn2+ reversibly abolished Ca2+ mobilization evoked by two additional stimuli: a decrease in extracellular pH or Na+ concentration. These findings support the hypothesis that the three stimuli (Cd2+ or a decrease in external pH or Na+ concentration) activate the same orphan receptor. Growth in high Zn2+ apparently desensitizes the cells to the Cd2+ receptor stimuli by repressing receptor synthesis.
Smith
L
L
Department of Pharmacology, School of Medicine, University of Alabama, Birmingham 35294.
Pijuan
V
V
Zhuang
Y
Y
Smith
J B
JB
D001920:Bradykinin / Q000494:pharmacology; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000378:metabolism; D013431:Sulfates / Q000494:pharmacology*; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology*; D019287:Zinc Sulfate
D002352:Carrier Proteins; D007295:Inositol Phosphates; D008565:Membrane Proteins; D013431:Sulfates; C076381:cadmium receptor; D002104:Cadmium; D019287:Zinc Sulfate; D003513:Cycloheximide; D015032:Zinc; D001920:Bradykinin; D002118:Calcium