Abstract
The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.
Highlights
The neuromuscular junction (NMJ) is a simple synapse between the motor nerve terminal and the surface of a muscle fiber sarcolemma, but is complex in its structure and function
This is the margin of safety, or safety factor of neuromuscular transmission, which allows the NMJ to continue to function under various physiological conditions and stresses
myasthenia gravis (MG) patients seronegative for Muscle-Specific Kinase (MuSK) and ACh receptors (AChRs) antibodies by radioimmunoprecipitation assay (RIA) may have antibodies to clustered AChRs by cell-based assay (CBA) (Leite et al, 2008)
Summary
The neuromuscular junction (NMJ) is a simple synapse between the motor nerve terminal and the surface of a muscle fiber sarcolemma, but is complex in its structure and function. Molecular Mechanisms of the NMJ muscle fibers express AChRs on their surface and the axons of motor neurons are guided to innervate the fibers, leading to the clustering of AChRs at high density underneath the motor nerve terminals. Despite being functionally active in the embryonic stage, NMJs undergo complex postnatal maturation during the first weeks of life that consist of an increase in size, morphological changes and the development of invaginations in the subsynaptic sarcolemma. The apparent macroscopic stability of the NMJ during adulthood hides numerous mechanisms that allow the homeostasis of the neuromuscular synapse in health and disease. This review covers the molecular mechanisms underlying the development and homeostasis of the NMJ and their contribution to health and disease
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