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Cadmium desynchronizes neurotransmitter release in the neuromuscular junction: Key role of ROS.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.freeradbiomed.2020.05.017 A N Tsentsevitsky 1 , G F Zakyrjanova 2 , A M Petrov 2
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.freeradbiomed.2020.05.017 A N Tsentsevitsky 1 , G F Zakyrjanova 2 , A M Petrov 2
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Cd2+ is one of the most widespread environmental pollutants and its accumulation in central and peripheral nervous systems leads to neurotoxicity as well as aggravation of common neurodegenerative diseases. Mechanism of the Cd2+ toxicity is far from being resolved. Here, using microelectrode recordings of postsynaptic responses and fluorescent redox indicators we studied the effect of Cd2+ in the submicromolar range on timing of neurotransmitter release and oxidative status in two functionally different compartments of the same frog motor nerve terminal. Cd2+ (0.1-1 μM) acting as typical voltage-gated Ca2+channel (VGCC) antagonist decreased neurotransmitter release in both distal and proximal parts of the nerve terminal, but in contrast to the VGCC blockers Cd2+(0.1-0.5 μM) desynchronized the release selectively in the distal region. The latter action of Cd2+ was completely prevented by inhibitor of NADPH-oxidase and antioxidants, including mitochondrial specific, as well as redox-sensitive TRPV1 channel blocker. Cd2+ markedly increased levels of mitochondrial reactive oxygen species (ROS) in both the distal and proximal compartments of the nerve terminal, which was associated with lipid peroxidation mainly in the distal region. Zn2+, whose transport systems translocate Cd2+, markedly enhanced the effects of Cd2+ on both the mitochondrial ROS levels and timing of neurotransmitter release. Furthermore, in the presence of Zn2+ ions, Cd2+ also desynchronized the neurotransmitter release in the proximal region. Thus, in synapses Cd2+ at very low concentrations can increase mitochondrial ROS, lipid peroxidation and disturb the timing of neurotransmitter release via a ROS/TRPV-dependent mechanism. Desynchronization of neurotransmitter release and synaptic oxidative stress could be early events in Cd2+ neurotoxicity.
中文翻译：
镉使神经肌肉接头中的神经递质释放失步：ROS的关键作用。
Cd2 +是最广泛的环境污染物之一，其在中枢和周围神经系统中的积累会导致神经毒性以及常见神经退行性疾病的恶化。Cd2 +毒性的机理尚待解决。在这里，使用突触后反应的微电极记录和荧光氧化还原指示剂，我们研究了在亚微摩尔范围内Cd2 +对同一只青蛙运动神经末梢的两个功能不同区室中神经递质释放时间和氧化状态的影响。作为典型的电压门控性Ca2 +通道（VGCC）拮抗剂的Cd2 +（0.1-1μM）减少了神经末梢和近端神经递质的释放，但与VGCC阻滞剂Cd2 +（0.1-0.5μM）相反，在远端区域选择性释放。Cad2 +的后一作用被NADPH-氧化酶和抗氧化剂（包括线粒体特异性）和氧化还原敏感的TRPV1通道阻滞剂的抑制剂完全阻止。Cd2 +明显增加了神经末梢和近端隔室中线粒体活性氧（ROS）的水平，这主要与远端区域的脂质过氧化有关。Zn2 +的转运系统易位于Cd2 +，可显着增强Cd2 +对线粒体ROS水平和神经递质释放时间的影响。此外，在存在Zn2 +离子的情况下，Cd2 +还会使近端区域的神经递质释放失步。因此，在突触中，低浓度的Cd2 +会增加线粒体ROS，脂质过氧化并通过ROS / TRPV依赖性机制干扰神经递质释放的时机。神经递质释放和突触氧化应激的不同步可能是Cd2 +神经毒性的早期事件。
更新日期：2020-05-21
中文翻译：
镉使神经肌肉接头中的神经递质释放失步：ROS的关键作用。
Cd2 +是最广泛的环境污染物之一，其在中枢和周围神经系统中的积累会导致神经毒性以及常见神经退行性疾病的恶化。Cd2 +毒性的机理尚待解决。在这里，使用突触后反应的微电极记录和荧光氧化还原指示剂，我们研究了在亚微摩尔范围内Cd2 +对同一只青蛙运动神经末梢的两个功能不同区室中神经递质释放时间和氧化状态的影响。作为典型的电压门控性Ca2 +通道（VGCC）拮抗剂的Cd2 +（0.1-1μM）减少了神经末梢和近端神经递质的释放，但与VGCC阻滞剂Cd2 +（0.1-0.5μM）相反，在远端区域选择性释放。Cad2 +的后一作用被NADPH-氧化酶和抗氧化剂（包括线粒体特异性）和氧化还原敏感的TRPV1通道阻滞剂的抑制剂完全阻止。Cd2 +明显增加了神经末梢和近端隔室中线粒体活性氧（ROS）的水平，这主要与远端区域的脂质过氧化有关。Zn2 +的转运系统易位于Cd2 +，可显着增强Cd2 +对线粒体ROS水平和神经递质释放时间的影响。此外，在存在Zn2 +离子的情况下，Cd2 +还会使近端区域的神经递质释放失步。因此，在突触中，低浓度的Cd2 +会增加线粒体ROS，脂质过氧化并通过ROS / TRPV依赖性机制干扰神经递质释放的时机。神经递质释放和突触氧化应激的不同步可能是Cd2 +神经毒性的早期事件。
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