Use-dependent potentiation of voltage-gated calcium channels rescues neurotransmission in nerve terminals intoxicated by botulinum neurotoxin serotype A
| Autor: | Katie M. Hoffman, James B. Machamer, Margaret R. Eisen, Phillip H. Beske, Patrick M. McNutt |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nervous system Synaptosomal-Associated Protein 25 Science Neuromuscular Junction Neuromuscular transmission Neurotransmission Serogroup Synaptic Transmission Article Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Paralysis Medicine Neuromuscular Agents Botulism Botulinum Toxins Type A Neurons Multidisciplinary Voltage-dependent calcium channel business.industry Excitatory Postsynaptic Potentials Long-term potentiation Anatomy medicine.disease Electrophysiology 030104 developmental biology medicine.anatomical_structure Synapses Calcium Calcium Channels Amifampridine business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-16064-3 |
| Popis: | Botulinum neurotoxins (BoNTs) are highly potent toxins that cleave neuronal SNARE proteins required for neurotransmission, causing flaccid paralysis and death by asphyxiation. Currently, there are no clinical treatments to delay or reverse BoNT-induced blockade of neuromuscular transmission. While aminopyridines have demonstrated varying efficacy in transiently reducing paralysis following BoNT poisoning, the precise mechanisms by which aminopyridines symptomatically treat botulism are not understood. Here we found that activity-dependent potentiation of presynaptic voltage-gated calcium channels (VGCCs) underlies 3,4-diaminopyridine (3,4-DAP)-mediated rescue of neurotransmission in central nervous system synapses and mouse diaphragm neuromuscular junctions fully intoxicated by BoNT serotype A. Combinatorial treatments with 3,4-DAP and VGCC agonists proved synergistic in restoring suprathreshold endplate potentials in mouse diaphragms fully intoxicated by BoNT/A. In contrast, synapses fully intoxicated by BoNT serotypes D or E were refractory to synaptic rescue by any treatment. We interpret these data to propose that increasing the duration or extent of VGCC activation prolongs the opportunity for low-efficiency fusion by fusogenic complexes incorporating BoNT/A-cleaved SNAP-25. The identification of VGCC agonists that rescue neurotransmission in BoNT/A-intoxicated synapses provides compelling evidence for potential therapeutic utility in some cases of human botulism. |
| Databáze: | OpenAIRE |
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