Defining potential roles of Pb2+ in neurotoxicity from a calciomics approach

Abstract

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., Pb²⁺) involves disruption of synaptic activity, and these observed effects are associated with the ability of Pb²⁺ to interfere with Zn²⁺ and Ca²⁺-dependent functions. However, the molecular mechanism behind Pb²⁺ toxicity remains a topic of debate. In this review, we first discuss potential neuronal Ca²⁺ binding protein (CaBP) targets for Pb²⁺ 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 Ca²⁺-signalling pathways. We then compare metal binding properties between Ca²⁺ and Pb²⁺ to understand the structural implications of Pb²⁺ binding to CaBPs. Statistical and biophysical studies (e.g., NMR and fluorescence spectroscopy) of Pb²⁺ binding are discussed to investigate the molecular mechanism behind Pb²⁺ toxicity. These studies identify an opportunistic, allosteric binding of Pb²⁺ to CaM, which is distinct from ionic displacement. Together, these data suggest three potential modes of Pb²⁺ activity related to molecular and/or neural toxicity: (i) Pb²⁺ can occupy Ca²⁺-binding sites, inhibiting the activity of the protein by structural modulation, (ii) Pb²⁺ can mimic Ca²⁺ in the binding sites, falsely activating the protein and perturbing downstream activities, or (iii) Pb²⁺ can bind outside of the Ca²⁺-binding sites, resulting in the allosteric modulation of the protein activity. Moreover, the data further suggest that even low concentrations of Pb²⁺ can interfere at multiple points within the neuronal Ca²⁺ signalling pathways to cause neurotoxicity.