Lead and other metals can substitute for Ca2+ in calmodulin

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Abstract
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. 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. Pb2+ can replace Ca2+ with respect to the calmodulin-dependent phosphorylation of brain membranes. With high Pb2+ concentrations, phosphorylation was inhibited. 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. 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.

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