Current concepts in neuromuscular transmission

The neuromuscular junction (NMJ) is structured and powered to transduce electrical activity from the distal nerve terminal of a motor neurone via the neuromuscular cleft to the post-junctional muscle membrane to ultimately generate muscle contraction. Our understanding of this complex function has expanded over many years, and the NMJ has served as a prototype for how different synapses operate in the peripheral and central nervous systems. The NMJ has a presynaptic part which is synonymous with the distal nerve ending, being responsible for neurotransmitter synthesis, packaging into vesicles, and subsequent vesicle transportation to active release sites where vesicle docking, fusion, and release of acetylcholine and other co-released transmitters finally take place. The synaptic cleft, filled with large molecular complexes that guarantee ultrastructural NMJ arrangement and signal transduction, allows for rapid diffusion and degradation of the neurotransmitter. The postsynaptic part consists of a folded muscle membrane into which nicotinic acetylcholine receptors (nAChRs) directly opposite the presynaptic active release sites are mounted and fixed by a cytoskeleton. This specialized postsynaptic region is closely associated with the perijunctional zone where a high density of sodium channels promote and amplify the signal in order to guarantee the propagation of the electrical activity to generate muscle contraction. The transduction process is maintained at load (i.e. high stimulus frequency) by a presynaptic mechanism allowing for sustained transmitter release over time at high demand. This positive feedback mechanism relies on neuronal nAChRs present on the distal nerve terminal, whereas the continuation of the transduction process at the postsynaptic part relies on the classical muscle type nAChR. In this review, we will focus on recent findings of potential clinical importance that will advance our understanding of the effects of neuromuscular blocking agents and neuromuscular monitoring and also our management of disorders of the neuromuscular system within anaesthesia and intensive care.