Transmembrane Signals and Protooncogene Induction Evoked by Carcinogenic Metals and Prevented by Zinc

Abstract

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)

Calcium signaling and cytotoxicity.

“…As a result of the prolonged inhibition of SERCA, the activation of the influx pathway leads to a massive accumulation of Ca2+, which is worsened by the additional inhibition of the PMCA, and subsequent death of thymocytes by apoptosis (Figure 4) (74). A similar mechanism has been reported for organotin-induced apoptosis of PC12 cells (77 Similarily, Ca2+ signaling processes may be targeted by toxic metals to cause a range of perturbations (78)(79)(80)(81)(82). For instance, inorganic mercury opens L-type Ca2+ channels and produces a sustained elevation of [Ca2+]j and death of PC12 cells (82).…”

Calcium Signaling and Cytotoxicity

“…As a result of the prolonged inhibition of SERCA, the activation of the influx pathway leads to a massive accumulation of Ca2+, which is worsened by the additional inhibition of the PMCA, and subsequent death of thymocytes by apoptosis ( Figure 4) (74). A similar mechanism has been reported for organotin-induced apoptosis of PC12 cells (77 Similarily, Ca2+ signaling processes may be targeted by toxic metals to cause a range of perturbations (78)(79)(80)(81)(82) (84)(85)(86). The pore complex has been localized to the contact sites between the inner and outer mitochondrial membranes.…”

Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells

“…In addition to interacting with thiols and influencing Ca2+ binding and signaling, Cd2+ has a number of other effects on cellular processes that probably contribute to its toxicity in certain circumstances. These include triggering apoptosis [Lohmann and Beyersmann, 1993;El Azzouzi et al, 19941 and causing variable changes in transcription of a number of oncogenes [Jin and Ringertz, 1990;Tang and Enger, 1993;Smith et al, 1994;Matsuoka and Call, 19951. In the present study we have not addressed the consequences of cytoskeletal disassembly to determine, for instance whether the Cd2+-treated cells retain normal patterns of gene transcription and proceed appropriately through the cell cycle upon removal of Cd2+ . Nevertheless, the rather profound change in filamentous actin elicited in smooth muscle and mesangial cells suggests that it could contribute to the toxicity of Cd2+ in these cells.…”