Reversible desensitization of fibroblasts to cadmium receptor stimuli: Evidence that growth in high zinc represses a xenobiotic receptor

Abstract

The xenobiotic Cd 2+ triggers the production of inositol trisphosphate and releases stored Ca 2+ in certain cell types, apparently by binding to a zinc site in the external domain of an “orphan” receptor (no known endogenous stimulus). Cd 2+ and bradykinin evoke similar spikes in cytosolic free Ca 2+. Growth in high Zn 2+ (100–200 μ M) abolished the free Ca 2+ spike evoked by Cd 2+ without affecting the spike produced by bradykinin. Growth in high Zn 2+ 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 Zn 2+. Growth in high Zn 2+ nearly prevented the stimulation of 45Ca 2+ efflux by Cd 2+ without affecting the stimulation of 45Ca 2+ efflux by bradykinin or histamine. Removing Zn 2+ from the culture medium and incubating the cells for several hours fully restored responsiveness to Cd 2+. Cycloheximide, actinomycin D, or tunicamycin prevented the restoration of Cd 2+ responsiveness, indicating that resensitization requires macromolecular synthesis. Growth in high Zn 2+ reversibly abolished Ca 2+ mobilization evoked by two additional stimuli: a decrease in extracellular pH or Na + concentration. These findings support the hypothesis that the three stimuli (Cd 2+ or a decrease in external pH or Na + concentration) activate the same orphan receptor. Growth in high Zn 2+ apparently desensitizes the cells to the Cd 2+ receptor stimuli by repressing receptor synthesis.