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Dual action of hydrogen peroxide on synaptic transmission at the frog neuromuscular junction

A. R. Giniatullin * and R. A. Giniatullin *†

There is evidence that reactive oxygen species (ROS) are produced and released during neuromuscular activity, but their role in synaptic transmission is not known. Using a two-electrode voltage-clamp technique, at frog neuromuscular junctions, the action H₂O₂ on end-plate currents (EPC) was studied to determine the targets for this membrane-permeable ROS. In curarized or cut muscles, micromolar concentrations of H₂O₂ increased the amplitude of EPCs. Higher (> 30 µM) doses inhibited EPCs and prolonged current decay. These effects were presynaptic since H₂O₂ did not change the amplitude or duration of miniature EPCs (although it reduced the rate of spontaneous release at high concentrations). Quantal analysis and deconvolution methods showed that facilitation of EPCs was due to increased quantal release, while depression was accompanied by temporal dispersion of evoked release. Extracellular recordings revealed prolonged presynaptic Ca²⁺ entry in the presence of high H₂O₂. Both low and high H₂O₂ increased presynaptic potentiation during high-frequency stimulation. Pro-oxidant Fe²⁺ did not affect facilitation by low doses of H₂O₂ but augmented the inhibition of EPCs by high H₂O_2, indicating involvement of hydroxyl radicals. High Mg²⁺ and the ROS scavenger N-acetylcysteine eliminated both the facilitatory and depressant effects of H₂O₂. The facilitatory effect of H₂O₂ was prevented by protein kinase C (PKC) inhibitors and 4-phorbol 12-myristate, 13-acetate (PMA), an activator of PKC. PKC inhibitors but not PMA also abolished the depressant effect of H₂O₂. Our data suggest complex presynaptic actions of H₂O₂, which could serve as a fast feedback modulator of intense neuromuscular transmission.

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