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Received for publication August 10, 2006.
Revised October 9, 2006.
Accepted for publication October 17, 2006.
The unique ability of a family of botulinum neurotoxins to specifically block neuro-exocytosis--by selective interaction with peripheral cholinergic nerve endings, endocytotic uptake, translocation to the cytosol and enzymic cleavage of essential proteins--underlies their increasing therapeutic applications. Although clinical use of type A is most widespread due to its prolonged inactivation of SNAP-25, botulinum neurotoxin E cleaves this same target but at a different bond and exhibits faster onset of neuromuscular paralysis. Herein, insights were gained into the different dynamics of action of types A and E toxins, which could help in designing variants with new pharmacological profiles. Natural and recombinant type E di-chain forms showed similar proteolytic and neuromuscular paralytic activities. The neuroparalysis induced by type E toxin was accelerated between 21 and 35 °C and attenuated by bafilomycin A1. Temperature elevation also revealed an unanticipated bipartite dose-response indicative of two distinct internalization processes, one being independent of temperature and the other dependent. Although elevating the temperature also hastened intoxication by type A, a second uptake mechanism was not evident. Increasing the frequency of nerve stimulation raised the uptake of type E via both processes, but the enhanced trafficking through the temperature-dependent pathway was only seen at 35 °C. These novel observations reveal that two membrane-retrieval mechanisms are operative at motor nerve terminals which type E toxin exploits to gain entry via an acidification-dependent step whereas A uses only one.
Key words:
Dystonia, Exo-endocytosis, Neuromuscular junction, Neurotransmission, SNAP-25, SNARE
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