Calmodulin-mediated cadmium inhibition of phosphodiesterase activity, in vitro.

Ion-stripped bovine brain calmodulin (CaM) binds 4 moles Cd2+ as well as 4 moles Ca2+ per mole protein, with similar affinity; in the presence of 1 mM Mg2+ the molar binding ratio of CaM for Ca2+ decreased to 3, the apparent K0.5 for Ca2+ nearly doubled, but the binding characteristics of CaM for Cd2+ were not changed. Saturating concentrations Ca2+ did not affect the molar binding ratio of CaM for Cd2+, but increased the apparent K0.5 for Cd2+; vice versa, saturating concentrations Cd2+ decreased the molar binding ratio for Ca2+ to 2 without affecting the apparent K0.5 for Ca2+. CaM-independent phosphodiesterase (PDE) activity was inhibited at [Cd2+] greater than 10(-5) M. Cd2+-CaM as well as Ca2+-CaM activated PDE. However, the Cd2+-CaM complex is less effective than the Ca2+-CaM complex in stimulating CaM-dependent enzyme activities. Cd2+ inhibits Ca2+- and CaM-dependent PDE in a competitive way. Introduction of Cd2+ in a medium containing Ca2+ and CaM may, therefore, result in a reduction of CaM-dependent enzyme stimulation. By its interference with Ca2+- and CaM- dependent PDE activity, Cd2+ could upset the catabolic pathway of cellular cyclic nucleotide metabolism.