Calmodulin-mediated cadmium inhibition of phosphodiesterase activity, in vitro

Abstract

Abstract. Ion-stripped bovine brain calmodulin (CaM) binds 4 moles Cd2 + as well as 4 moles Ca2 + per mole pro tein, with similar affinity; in the presence of 1 mM Mg2 + the molar binding ratio of CaM for Ca2 + decreased to 3, the apparent K05 for Ca2 + nearly doubled, but the binding i characteristics of CaM for Cd" + were not changed. Satu rating concentrations Ca2 + did not affect the molar bind ing ratio of CaM for Cd2 + , but increased the apparent K05 for Cd2+; vice versa, saturating concentrations Cd2+ de creased the molar binding ratio for Ca2+ to 2 without af fecting the apparent K0 5 for Ca2 + .CaM-independent phosphodiesterase (PDE) activity was inhibited at [Cd2 + ] > 10-5 M. Cd2^ -CaM as well as Ca2 + -CaM activated PDE. However, the Cd: + -CaM com plex is less effective than the Ca: + -CaM complex in stimu lating CaM-dependent enzyme activities. Cd2+ inhibits Ca2 + -and CaM-dependent PDE in a competitive way. In troduction of Cd2 + in a medium containing Ca2 1 and CaM may, therefore, result in a reduction of CaM-dependent enzyme stimulation.By its interference with Ca2 + -and CaM-dependent PDE activity, Cd~f could upset the catabolic pathway of cellular cyclic nucleotide metabolism.

Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines

“…In cell-free in vitro studies, at high concentrations (>50 μM) cadmium binds CaM and inhibits PDE activity. At low concentrations (<50 μM), similar to what is used in this study, cadmium binds CaM and activates PDE activity (Suzuki et al, 1985; Flik et al, 1987). Thus, we next examined whether the calmodulin-dependent PDE pathway mediates cadmium’s effect the specific osteoblast endpoints of apoptosis and alkaline phosphatase (ALP) activity.…”

Induction of c-fos Proto-oncogene in Mesangial Cells by Cadmium

“…Occupancy of these sites activates the Ca 2ϩ -calmodulin complex to interact with a number of other proteins including CaMK II and myosin light chain kinase and in turn affect their activity (46). In vitro Cd 2ϩ can induce conformational changes in calmodulin and activate calmodulin-dependent phosphodiesterase (47)(48)(49), a property it shares with other metal ions with similar ionic radii (47). Activation occurs even in the presence of physiological concentrations of glutathione (50) but requires a minimum concentration of Cd 2ϩ of approximately 10 M to become significant (47,48).…”

“…In vitro Cd 2ϩ can induce conformational changes in calmodulin and activate calmodulin-dependent phosphodiesterase (47)(48)(49), a property it shares with other metal ions with similar ionic radii (47). Activation occurs even in the presence of physiological concentrations of glutathione (50) but requires a minimum concentration of Cd 2ϩ of approximately 10 M to become significant (47,48). It has been postulated that increased activity of myosin light chain kinase contributes to the vascular toxicity of cadmium (51) The "classical" isoforms (␣, ␤I, ␤II, ␥) of PKC are Ca 2ϩ -dependent (57).…”

Cadmium inhibition of Ca2+ uptake in rainbow trout gills

“…In Cd2+ accumulation studies it was shown that Cd2+ enters the epithelial cell. The delay in producing an inhibitory effect could be due to Cd2+ buffering by cyto solic proteins such as metallothionein, glutathione, and calmodulin (sulfhydryl-and carboxylate-rich proteins that bind Cd2+ tightly) (8,13,27). This Cd2+ buffering could prevent inhibition of the Ca2+ transport ATPase by sequestering Cd2+ to no-effect levels during early exposure.…”