Accession Number:

AD1098885

Title:

Use-Dependent Potentiation of Voltage-Gated Calcium Channels Rescues Neurotransmission in Nerve terminals Intoxicated by Botulinum Neurotoxin Serotype A

Descriptive Note:

Journal Article - Open Access

Corporate Author:

US Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground United States

Personal Author(s):

• Beske,Phillip H.
• Hoffman,Katie M.
• Machamer,James B.
• Eisen,Margaret R.
• McNutt,Patrick M.

Report Date:

2017-11-20

Pagination or Media Count:

12.0

Abstract:

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 supra threshold endplate potentials in mouse diaphragms fully intoxicated by BoNTA. 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 BoNTA-cleaved SNAP-25. The identification of VGCC agonists that rescue neurotransmission in BoNTA-intoxicated synapses provides compelling evidence for potential therapeutic utility in some cases of human botulism.

Descriptors:

• neurotoxins
• cleavage
• paralysis
• neuromuscular agents
• biomedical research
• botulism
• electrophysiology
• nervous system
• therapy
• synapses

Subject Categories:

• Weapons Effects (Biological)

Distribution Statement:

APPROVED FOR PUBLIC RELEASE