Abstract
Neuromuscular junctions (NMJs) are directly involved into such indispensable to life processes as respiration and locomotion. However, motor nerve forms only one synaptic contact at each muscle fiber. This unique configuration requires specific properties and constrains to be effective. The very high density of acetylcholine receptors (AChRs) of muscle type in synaptic cleft and an excess of acetylcholine (ACh) released under physiological conditions make this synapse extremely reliable. Nevertheless, under pathological conditions such as myasthenia gravis and congenital myasthenic syndromes, the safety factor can be markedly reduced. Drugs used for short-term symptomatic therapy of these pathological states, cause partial inhibition of cholinesterases (ChEs). These enzymes catalyze the hydrolysis of ACh, thus terminate its action on AChRs. Extension of the lifetime of ACh molecules compensates muscular AChRs abnormalities and, consequently, rescues muscle contractions. In this mini review, we will first outline the functional organization of the NMJ, and then, consider the concept of the safety factor and how it may be changed. This will be followed by a look at autoregulation of ACh release that influences the safety factor of NMJs. Finally, we will consider the morphological features of NMJs as a putative reserve to increase effectiveness of pathological muscle weakness therapy by ChEs inhibitors due to opportunity to use micro-pharmacodynamic mechanisms.
Highlights
Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology
This will be followed by a look at autoregulation of ACh release that influences the safety factor of Neuromuscular junctions (NMJs)
NMJ is a tripartite synapse because three to five terminal Schwann cells (TSCs) covering each nerve terminal actively participate in the process of neuromuscular synaptic transmission (Robitaille, 1995; Robitaille et al, 1997; Rochon et al, 2001; Todd et al, 2007, 2010; Ko and Robitaille, 2015; Arbour et al, 2017; Heredia et al, 2018)
Summary
Neuromuscular junction (NMJ) is a synapse made up of motor axon branch (so-called nerve terminal), synaptic cleft, and postsynaptic region of muscle fiber (so-called end-plate), which is a folded structure where primary and secondary folds are distinguished. Such a configuration provides multiple extension of surface area allowing a huge density of receptors, ionic channels, and cholinesterases (ChEs) in a small crowded space (Figure 1). The time necessary for the whole system to recover determines the lability of synapse, i.e., the ability to reproduce the specific for each muscle pattern of excitation This time depends on the rate of enzymatic ACh hydrolysis. BChE, in turn, controls the spillover and dynamics of ACh outside synaptic cleft
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