Structural Factors Influencing the Efficacy of Neuromuscular Transmission


Address for correspondence: Professor Clarke R. Slater, Institute of Neuroscience, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Voice: +44-191-222-5732; fax: +44-191-222-5227.


Neuromuscular junctions (NMJs) in different species share many features of structure and function. At the same time, important differences distinguish, for example, human NMJs from those in other species. An understanding of the biological context of the human NMJ helps in the interpretation of the effects of disease on the biophysical properties of neuromuscular transmission. Many NMJs consist of a number of spot-like synaptic regions 1–5 μm across. Usually only a few multimolecular “quanta” of transmitter are released from each presynaptic “bouton” by a single nerve impulse. The total number of quanta released from an NMJ is roughly proportional to its total area. For example, human NMJs are about 10-fold smaller than those in frogs and release about 20 quanta/impulse versus 100–200 in frog NMJ. Although human NMJs release relatively few quanta, the effect of the transmitter is amplified by the high density of voltage-gated sodium channels (NaV1.4) in the highly folded postsynaptic membrane. A genetic influence on NMJ size has recently been discovered in some patients with limb-girdle myasthenia (LGM). Mutations of the gene encoding Dok-7, an essential component of the agrin–muscle-specific kinase pathway that controls postsynaptic differentiation at the mammalian NMJ, results in impaired transmission because the NMJs are abnormally small and have reduced folding but have a normal local density of normal acetylcholine receptors. This condition emphasizes the importance of structural features in achieving reliability of neuromuscular transmission.