Importance of Full-Collapse Vesicle Exocytosis for Synaptic Fatigue-Resistance at Rat Fast and Slow Muscle Neuromuscular Junctions

Jane E. Rudling, Benjamin D Drever, Brian Reid, Guy S. Bewick* (Corresponding Author)

*Corresponding author for this work

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Neurotransmitter release during trains of activity usually involves two vesicle pools (readily releasable pool, or RRP, and reserve pool, or RP) and two exocytosis mechanisms (“full-collapse” and “kiss-and-run”). However, synaptic terminals are adapted to differing patterns of use and the relationship of these factors to enabling terminals to adapt to differing transmitter release demands is not clear. We have therefore tested their contribution to a terminal’s ability to maintain release, or synaptic fatiguability in motor terminals innervating fast-twitch (fatiguable), and postural slow-twitch (fatigue-resistant) muscles. We used electrophysiological recording of neurotransmission and fluorescent dye markers of vesicle recycling to compare the effects of kinase inhibitors of varying myosin light chain kinase (MLCK) selectivity (staurosporine, wortmannin, LY294002 & ML-9) on vesicle pools, exocytosis mechanisms, and sustained neurotransmitter release, using postural-type activity train (20 Hz for 10 min) in these muscles. In both muscles, a small, rapidly depleted vesicle pool (the RRP) was inhibitor insensitive, continuing to release FM1-43, which is a marker of full-collapse exocytosis. MLCK-inhibiting kinases blocked all remaining FM1-43 loss from labelled vesicles. However, FM2-10 release only slowed, indicating continuing kiss-and-run exocytosis. Despite this, kinase inhibitors did not affect transmitter release fatiguability under normal conditions. However, augmenting release in high Ca2+ entirely blocked the synaptic fatigue-resistance of terminals in slow-twitch muscles. Thus, full-collapse exocytosis from most vesicles (the RP) is not essential for maintaining release during a single prolonged train. However, it becomes critical in fatigue-resistant terminals during high vesicle demand.
Original languageEnglish
Article number1936
Journal International Journal of Molecular Sciences
Issue number7
Early online date2 Jul 2018
Publication statusPublished - 2018

Bibliographical note

We would like to thank Dr Robert Banks, Prof Arild Njå and Prof Bill Wisden and Dr Phil Sheard for their helpful comments and discussions during the preparation of this manuscript, as well as for the contributions made by undergraduate students Alison Cuthbert, Richard McWilliam and Karen Peters, who helped produce initial observations prompting this study. This work was supported by grants from the
Biotechnology and Biological Science Research Council of the UK (BBSRC-1/511921) and The Wellcome Trust (WT-057994/2/99/Z).


  • synaptic transmission
  • neuromuscular junction
  • myosin light chain kinase
  • FM1-43


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