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Issue 6, 2016
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Defining potential roles of Pb2+ in neurotoxicity from a calciomics approach

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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.

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

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Publication details

The article was received on 15 Feb 2016, accepted on 01 Apr 2016 and first published on 07 Apr 2016


Article type: Minireview
DOI: 10.1039/C6MT00038J
Citation: Metallomics, 2016,8, 563-578
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    Defining potential roles of Pb2+ in neurotoxicity from a calciomics approach

    R. Gorkhali, K. Huang, M. Kirberger and J. J. Yang, Metallomics, 2016, 8, 563
    DOI: 10.1039/C6MT00038J

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