Defining potential roles of Pb super(2+) in neurotoxicity from a calciomics approach

Metal ions play crucial roles in numerous biological processes, facilitating biochemical reactions by binding to various proteins. An increasing body of evidence suggests that neurotoxicity associated with exposure to nonessential metals (e.g., Pb super(2+)) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb super(2+) to interfere with Zn super(2+) and Ca super(2+)-dependent functions. However, the molecular mechanism behind Pb super(2+) toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca super(2+) binding protein (CaBP) targets for Pb super(2+) such as calmodulin (CaM), synaptotagmin, neuronal calcium sensor-1 (NCS-1), N-methyl-d-aspartate receptor (NMDAR) and family C of G-protein coupled receptors (cGPCRs), and their involvement in Ca super(2+)-signalling pathways. We then compare metal binding properties between Ca super(2+) and Pb super(2+) to understand the structural implications of Pb super(2+) binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb super(2+) binding are discussed to investigate the molecular mechanism behind Pb super(2+) toxicity. These studies identify an opportunistic, allosteric binding of Pb super(2+) to CaM, which is distinct from ionic displacement. Together, these data suggest three potential modes of Pb super(2+) activity related to molecular and/or neural toxicity: (i) Pb super(2+) can occupy Ca super(2+)-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb super(2+) can mimic Ca super(2+) in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb super(2+) can bind outside of the Ca super(2+)-binding sites, resulting in the allosteric modulation of the protein activity. Moreover, the data further suggest that even low concentrations of Pb super(2+) can interfere at multiple points within the neuronal Ca super(2+) signalling pathways to cause neurotoxicity.