Safety factor at the neuromuscular junction
Section snippets
Neuromuscular transmission is a highly reliable process
The transmission of signals from nerve to muscle is an extremely reliable process. In normal humans, no indication of a failure of neuromuscular transmission is seen even during the most extreme voluntary exertion. This is mainly because more transmitter is released from the motor nerve terminal by each nerve impulse than is required to excite the muscle fibre. This ensures that during prolonged, high-frequency activation of muscles, when the amount of transmitter released per nerve impulse
Functional organisation of the NMJ
Many features of the structural and functional organisation of the NMJ influence the safety factor. Excellent detailed descriptions of the anatomy of the neuromuscular junction can be found elsewhere (Couteaux, 1973, Salpeter, 1987, Engel, 1994b). Here, we describe briefly the main structural features of the NMJ.
Origin of the concept of a safety factor in excitable cells
The reliability of neuromuscular transmission normally results from the release of more quanta of ACh than are required to initiate an action potential. The term safety factor (or safety margin-the terms are used interchangeably) for neuromuscular transmission is used to describe this excess. However, the concept of safety factor for cell excitation was initially developed in the context of the initiation and propagation of action potentials in myelinated axons. Early experimental studies
Estimating safety factor at the NMJ
For most definitions of safety factor, estimating its value requires assessing both the amount of transmitter released per nerve impulse and the amount of transmitter required to initiate an action potential. The many technical problems associated with direct biochemical measurement of ACh released from motor nerve terminals have led most workers to estimate transmitter release from electrophysiological recordings of postsynaptic effects. From such recordings, it is possible to obtain an
Features of the NMJ that influence safety factor
The safety factor of neuromuscular transmission is influenced by many features of the pre- and postsynaptic components of the NMJ. Some of these features are structural and likely to be relatively stable on a time scale of minutes or hours. Others are more dynamic and reflect physiological changes within the cells on a much more rapid time scale.
Biological variation and safety factor
Normal vertebrate neuromuscular junctions vary greatly in their size and form. Consistent variations exist between NMJs in different species, in muscles of different function in the same species, and in different stages of development. In each case, the observed structural variations are likely to have an important impact on the safety factor.
Pathology of the safety factor
The complexity of neuromuscular transmission means that there are many points at which the safety factor can be compromised. Numerous diseases have been described, each quite rare, which are characterised by an impairment of neuromuscular transmission resulting in a weakness of voluntary contraction. These are known collectively as myasthenias or myasthenic syndromes. Some myasthenias are acquired autoimmune conditions in which antibodies are produced which interact with synaptic molecules (
Conclusions
In this review of the safety factor at the neuromuscular junction, we have intentionally concentrated on observations made at vertebrate, mostly mammalian, NMJs. Not only is there more detailed information about the normal structure and function of these NMJs than in most other species but there is also a growing body of information about how mammalian NMJs develop and how they may be affected by pathological conditions. Consideration of this information suggests a number of conclusions
Acknowledgements
Our own work referred to in this review has been supported by grants from the Muscular Dystrophy Group, The Royal Society and the Wellcome Trust. We are grateful to Chris Bailey, John Harris and Ki Pang for their reading and commenting on this review.
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