Lead and other metals can substitute for Ca²⁺ in calmodulin

We have studied the interaction between some heavy metal ions, as compared with earth alkali ions, and calmodulin, a tissue protein which binds Ca²⁺ and mediates some of its effects. 1. Calmodulin dependent phosphodiesterase was activated with Pb²⁺, Ca²⁺, Sr²⁺, Ba²⁺, and Cd²⁺ (EC₅₀ about 0.8 μM). The maximal activation achieved decreases in the order given. Hg²⁺ Sn²⁺, Fe²⁺, Cu²⁺, Ni²⁺, Bi³⁺, and Sb³⁺ up to 20 μM did not activate. 2. Pb²⁺ can replace Ca²⁺ with respect to the calmodulin-dependent phosphorylation of brain membranes. With high Pb²⁺ concentrations, phosphorylation was inhibited. 3. Calmodulin binding to brain membranes was enhanced with concentrations below 10^-4 M in the following order: Pb²⁺ ≧Ca²⁺ ∼ Sr²⁺ > Cd²⁺ > Mn²⁺ > Ba²⁺. In contrast Mg²⁺, Hg²⁺, Sn²⁺, Fe²⁺, Ni²⁺, Co²⁺, and Cu²⁺ triggered, if at all, a non-saturable binding of calmodulin. 4. In the flow-dialysis, other ions competed with ⁴⁵Ca²⁺ binding to calmodulin in the following order: Pb²⁺ ∼ Ca²⁺ > Mn²⁺, Ba²⁺, Cd²⁺, Sr²⁺. Thus among the ions investigated Pb²⁺ is a fully potent substitute for Ca²⁺ in every calmodulin-dependent reaction investigated. Cd²⁺ is always much less potent. The earth alkali ions Sr²⁺ and Ba²⁺ take an intermediate position. It remains to be shown whether calmodulin is merely a storage site for Pb²⁺, or whether the resulting functional changes play a role in Pb²⁺ poisoning.