Defining potential roles of Pb(2+) in neurotoxicity from a calciomics approach.
Defining potential roles of Pb(2+) in neurotoxicity from a calciomics approach.
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DOI：
10.1039/c6mt00038j
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发表时间：
2016-06-01
期刊：
影响因子：
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通讯作者：
Yang JJ
中科院分区：
文献类型：
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作者：
Gorkhali R;Huang K;Kirberger M;Yang JJ
金属离子在许多生物过程中起着至关重要的作用，通过与各种蛋白质结合来促进生物化学反应。越来越多的证据表明，与暴露于非必需金属（例如，Pb2+）相关的神经毒性涉及突触活动的破坏，这些观察到的影响与Pb2+干扰Zn2+和Ca2+依赖功能的能力有关。然而，Pb2+毒性背后的分子机制仍然是一个有争议的话题。在这篇综述中，我们首先讨论了Pb2+的潜在神经元Ca2+结合蛋白（CaBP）靶点，如钙调蛋白（CaM）、突触tagmin、神经元钙传感器-1 （NCS-1）、n -甲基- d -天冬氨酸受体（NMDAR）和g蛋白偶联受体（cGPCRs）家族C，以及它们在Ca2+信号通路中的作用。然后，我们比较了Ca2+和Pb2+之间的金属结合特性，以了解Pb2+与cabp结合的结构意义。讨论了Pb2+结合的统计和生物物理研究（例如，核磁共振和荧光光谱），以研究Pb2+毒性背后的分子机制。这些研究确定了Pb2+与CaM的机会性变构结合，这与离子位移不同。总之，这些数据表明Pb2+活性与分子和/或神经毒性相关的三种潜在模式：(i) Pb2+可以占据Ca2+结合位点，通过结构调节抑制蛋白质的活性；（ii） Pb2+可以在结合位点模仿Ca2+，错误地激活蛋白质并扰乱下游活性；（iii） Pb2+结合在Ca2+结合位点外，导致蛋白质活性的变构调节。此外，数据进一步表明，即使是低浓度的Pb2+也可以干扰神经元Ca2+信号通路中的多个点，从而引起神经毒性。
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+ with CaM that is distinct from ionic displacement. Together, this data suggests 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+ binds outside of the Ca2+-binding sites, resulting in allosteric modulation of the proteins 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.