Evidence that lead acts as a calcium substitute in second messenger metabolism.
Our investigations of the ability of lead to substitute for calcium in several intracellular regulatory events are reviewed in the context of the neurotoxicity produced by this heavy metal. We found that lead activates calmodulin dependent phosphodiesterase, calmodulin inhibitor sensitive potassium channels, and calmodulin independent protein kinase C (PKC). Because of sensitivity in the picomolar range, the activation of PKC by lead may be more biologically relevant than its activation of calmodulin which requires high nanomolar levels of the toxicant. We also found that inhibition of capillary-like structure formation in co-cultures of neural endothelial cells with astrocytes by lead was similar to that produced by phorbol esters, known stimulators of PKC. This functional event supports the hypothesis that PKC activation underlies some aspects of lead neurotoxicity. Taken together these studies implicate second messenger metabolism and protein kinase activation as potential sites for the disruptive action of lead upon nervous system function. These reactions could contribute to the subtle defects in brain function associated with low level poisoning.