中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (9): 1762-1763.doi: 10.4103/1673-5374.306067

• 观点:周围神经损伤修复保护与再生 • 上一篇    下一篇

镉神经毒性的突触机制

  

  • 出版日期:2021-09-15 发布日期:2021-02-05

Synaptic mechanisms of cadmium neurotoxicity

Andrei N. Tsentsevitsky, Alexey M. Petrov*   

  1. Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center ‘’Kazan Scientific Center of RAS”, 2/31 Lobachevsky Street, Box 30, Kazan, 420111, Russia (Tsentsevitsky AN, Petrov AM) 
    Institute of Neuroscience, Kazan State Medial University, 49 Butlerova Street, Kazan, 420012, Russia (Petrov AM)
  • Online:2021-09-15 Published:2021-02-05
  • Contact: Alexey M. Petrov, PhD, aleksey.petrov@kazangmu.ru.
  • Supported by:
    The present work was supported in part by the Russian Foundation for Basic Research grant # 20-04-00077 (to AMP) and partially the government assignment for FRC Kazan Scientific Center of RAS.

摘要: https://orcid.org/0000-0002-1432-3455
(Alexey M. Petrov)

Abstract: Cadmium (Cd) is a toxic heavy metal ubiquitously distributed in the environment (water, air, food, smoke) with extreme ability to accumulate in the human body due to its delayed clearance (half-life time 15–30 years). Consequently, prolonged exposure to low doses of Cd causes multi-organ toxicity. Remarkably, the central and peripheral nervous systems are considered as one of the most vulnerable targets. Excessive Cd exposure can profoundly aggravate common neurodegenerative diseases and peripheral polyneuropathies as well as lead to mental deficits in children (Branca et al., 2020). Conceivably, that Cd-induced defects in communication between neurons could be triggering events in Cd neurotoxicity. Numerous studies have discovered the disturbances at the synaptic levels in response to both acute and chronic Cd administration. Furthermore, release of Cd, captured by neuronal tissue, into extracellular space is increased by stimulation of synaptic vesicle (SV) exocytosis (Minami et al., 2001), pointing to Cd accumulation within the SVs in presynaptic terminals. Being a divalent cation, Cd can enter cells through various ways (such as active transporters, carriers, channels, and endocytosis), which serve to transport physiologically essential cations (Ca, Mg, Cu, Mn, Zn). An important route for Cd penetration into neuronal cells relies on zinc transporters (ZnTs). Among them, ZnT3 is highly abundant in the membranes of the SVs and responsible for maintaining the vesicular Zn pool in brain (McAllister and Dyck, 2017). Presumably, presynaptic terminals containing from hundreds to thousands of SVs could be reservoirs for Cd accumulating in the SVs due to ZnT3 activity. Furthermore, SV membranes are enriched with anionic negatively-charged lipids that can electrostatically attract bivalent cations, including Cd. Likewise, voltage-gated Ca2+ channels (VGCCs), which are reversibly blocked by Cd, reside densely at the presynaptic site can concentrate Cd, facilitating its uptake. Moreover, Cd may slowly pass into the cytosol through some of the VGCCs. Inside the nerve terminals Cd could affect a plethora of processes, consequently disturbing various presynaptic functions, notably neurotransmitter release. The resulting synaptic defects can produce “devastating signals” which are propagated to the neuronal bodies. Such retrograde pattern of pathology spreading is observed in some neurodegenerative disorders. Recently, we have found that at very low concentrations Cd can desynchronize neurotransmitter release from motor nerve terminals (Tsentsevitsky et al., 2020). A focus on the mechanism behind this phenomenon (Figure 1) can delineate the early events in Cd neurotoxicity and reveal a bridge between Cd action and neurodegeneration.