SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release.
Reactive oxygen species (ROS) participate in various physiological and pathological processes in the nervous system, but the specific pathways that mediate ROS signalling remain largely unknown. Using electrophysiological techniques and biochemical evaluation of isolated fusion proteins, we explored the sensitivity to standard oxidative stress of the entire synapse, the pre-synaptic machinery and essential fusion proteins underlying transmitter exocytosis. Oxidative stress induced by H(2)O(2) plus Fe(2+) inhibited both evoked and spontaneous quantal release from frog or mouse motor nerve endings, while it left post-synaptic sensitivity unchanged. The depressant effect of H(2)O(2) on acetylcholine release was pertussis toxin-insensitive, ruling out G-protein cascades. Experiments with ionomycin, a Ca(2+) ionophore, revealed that ROS directly impaired the function of releasing machinery. In line with this, SNAP25, one of three essential fusion proteins, showed a selectively high sensitivity to the oxidative signals. Several ROS scavengers enhanced evoked synaptic transmission, consistent with tonic inhibition by endogenous ROS. Our data suggest that ROS-induced impairment of releasing machinery is mediated by SNAP25, which appears to be a pre-synaptic ROS sensor. This mechanism of ROS signalling could have widespread implications in the nervous system and might contribute to the pathogenesis of neurodegenerative diseases.
Giniatullin
A R
AR
Kazan Medical University, Tatarstan, Russia. Rashid@sissa.it
Darios
F
F
Shakirzyanova
A
A
Davletov
B
B
Giniatullin
R
R
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism; D005296:Ferrous Compounds / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D009045:Motor Endplate / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D050825:Synaptosomal-Associated Protein 25 / Q000502:physiology*
D000975:Antioxidants; D005296:Ferrous Compounds; D016166:Free Radical Scavengers; D007476:Ionophores; D018377:Neurotransmitter Agents; D016877:Oxidants; D017382:Reactive Oxygen Species; D050825:Synaptosomal-Associated Protein 25; D017665:Hydroxyl Radical; D015759:Ionomycin; D006861:Hydrogen Peroxide