Dual Action of Hydrogen Peroxide on Synaptic Transmission at the Frog Neuromuscular Junction

Abstract

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 H2O2, 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 4β‐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.

A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction

“…In addition to being a classic oxidative stress paradigm, H 2 O 2 has been shown to modulate neuromuscular activity in vertebrates (Giniatullin and Giniatullin 2003) and manipulate neuronal signal transduction in mammalian cell culture (Chai and Lin 2010). This study exposed Drosophila larval NMJ preparations to 2.25 mM H 2 O 2 and demonstrates that PKG manipulation alters synaptic transmission tolerance to acute oxidative toxicity.…”

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…ROS in neurons also enhances voltagegated K + currents elicited by NGF, mediated by activation of NF-kappaB [149]. H 2 O 2 inhibits synaptic transmission in hippocampus and other areas of the brain [150,151] by complex mechanisms that are not yet fully elucidated [152,153]. In guinea pig striatal slices, H 2 O 2 production was Ca 2+ -dependent and modulated neurotransmitter release, revealing a signaling role for ROS in synaptic transmission [154].…”

SNAP-25 Contains Non-Acylated Thiol Pairs that can Form Intrachain Disulfide Bonds: Possible Sites for Redox Modulation of Neurotransmission

“…Oxidative stress inhibits neurotransmitter release (Gilman et al 1992;Zoccarato et al 1995;Zoccarato and Alexandre 1996;Chen et al 2001;Giniatullin and Giniatullin 2003). Moreover, oxidative stress and impaired synaptic transmission are correlates of aging and the early stages of neurodegenerative disease (Keating 2008).…”