Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc.
Cd2+ provokes an immediate production of inositol trisphosphate and the release of Ca2+ from internal stores in human fibroblasts and some other mammalian cells. Ni2+, Co2+, Fe2+, and Mn2+ evoke the release of stored Ca2+, but are less potent than Cd2+ (apparent K0.5 = 40 nM). Zn2+ and Cu2+ competitively inhibit Ca2+ release evoked by Cd2+ without affecting Ca2+ release by hormones such as bradykinin. Zn2+ has the same apparent Ki value (80-90 nM) towards the five agonist metals, which suggests that the metals interact with the same site. Many other divalent cations neither released stored Ca2+ nor affected Cd(2+)-evoked Ca2+ release. The agonist metals appear to activate phospholipase C via a G protein rather than a tyrosine kinase. The production of reactive oxygen species is probably not involved in Ca2+ release by the metals. Cd2+ and other stimuli that raise cytosolic-free Ca2+ induce cyclic (AMP) production, apparently by activating a calmodulin-dependent adenylyl cyclase. We suggest that an orphan receptor mediates the hormonelike responses to Cd2+ and the other agonist metals. The receptor is referred to as an orphan because its physiological stimulus is unknown. Growth of the fibroblasts in high Zn2+ desensitizes them to the five agonist metals without affecting Ca2+ release by bradykinin or histamine. A several hour incubation in culture medium with normal Zn2+ fully restores responsiveness to the five active metals. Growth in high Zn2+ appears to repress the synthesis of the putative orphan receptor because inhibitors of RNA or protein synthesis, or asparagine-linked glycosylation, prevented the restoration of metal responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, School of Medicine, University of Alabama at Birmingham 35294.
J B
JB
Smith
L
L
Smith
V
V
Pijuan
Y
Y
Zhuang
Y C
YC
Chen
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008670:Metals / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011519:Proto-Oncogenes / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D008670:Metals; D015032:Zinc