Cadmium desynchronizes neurotransmitter release in the neuromuscular junction: Key role of ROS

Abstract 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.