Safety factor at the neuromuscular junction

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Abstract

Reliable transmission of activity from nerve to muscle is necessary for the normal function of the body. The term ‘safety factor’ refers to the ability of neuromuscular transmission to remain effective under various physiological conditions and stresses. This is a result of the amount of transmitter released per nerve impulse being greater than that required to trigger an action potential in the muscle fibre. The safety factor is a measure of this excess of released transmitter. In this review we discuss the practical difficulties involved in estimating the safety factor in vitro. We then consider the factors that influence the safety factor in vivo. While presynaptic transmitter release may be modulated on a moment to moment basis, the postsynaptic features that determine the effect of released transmitter are not so readily altered to meet changing demands. Different strategies are used by different species to ensure reliable neuromuscular transmission. Some, like frogs, rely on releasing a large amount of transmitter while others, like man, rely on elaborate postsynaptic specialisations to enhance the response to transmitter. In normal adult mammals, the safety factor is generally 3–5. Both pre- and postsynaptic components change during development and may show plasticity in response to injury or disease. Thus, both acquired autoimmune and inherited congenital diseases of the neuromuscular junction (NMJ) can significantly reduce, or even transiently increase, safety factor.

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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