Pb(II) Disruption of Synaptic Activity Through Ca(II)- and Zn(II)-binding Proteins

Metal toxicity is a pervasive global health problem due to the increasing bioavailability of non-essential metals released into the environment as a result of human industry. Neurotoxicity occurs at the molecular level through various mechanisms of metal dyshomeostasis, resulting in acute and chronic systemic pathologies. Research in our laboratory and others has demonstrated that divalent lead (Pb 2+ ) can replace numerous essential metals in proteins, including both Ca 2+ and Zn 2+ , which play prominent roles in neural activities. The promiscuous nature of Pb 2+ ions is likely due to the polarizable nature of the ion which allows it to readily conform to a variety of different metal binding geometries and coordination numbers, and bind opportunistically in regions of proteins outside of known metal binding sites, which may alter protein structure and allosterically inhibit function. Because Pb 2+ is deeply entwined in Ca 2+ -regulated activities, and given the extensive and integral involvement of Ca 2+ -signaling in neural pathways, the purpose of this brief review is to highlight recent research efforts to understand the mechanisms through which Pb 2+ can interfere with neurotransmission and synaptic activity in Ca 2+ - and Zn 2+ -signaling pathways in neurons.