Junctional folds

FIGURE 43-2 Photomicrograph of the human neuromuscular junction. In normal muscle, Ach receptors are associated with the terminal expansions of the junctional folds and the architecture of the postjunctional membrane follows closely the distribution of active zones in the presynaptic membrane, b, basal lamina I, infoldings m, mitochondria M, myocyte N, nerve terminal r, ribosomes s, synaptic space S, Schwann cell. Courtesy of A. Engel. 

Slow-channel syndrome. Abnormally long-lived openings of mutant AChR channels result in prolonged endplate currents and potentials, which in turn elicit one or more repetitive muscle action potentials of lower amplitude that decrement. The morphologic consequences stem from prolonged activation of the AChR channel that causes cationic overload of the postsynaptic region - the endplate myopathy - with Ca2+ accumulation, destruction of the junctional folds, nuclear apoptosis, and vacuolar degeneration of the terminal. Some slow-channel mutations in the transmembrane domain of the AChR render the channel leaky by stabilization of the open state, which is populated even in the absence of ACh. Curiously, some slow-channel mutants can be opened by choline even at the concentrations that are normally present in serum. Quinidine, an open-channel blocker of the AchR, is used for therapy. 

ACh receptor These are located on the peaks of the junctional folds of the muscle membrane as shown. They are also found presynaptically on the nerve terminal, where, once activated, they promote migration of ACh vesicles from deep to superficial stores. 

Acetylcholinesterase (AChE) This enzyme is found in the troughs of the junctional folds of the muscle membrane and is responsible for metabolizing ACh within the synaptic cleft. 

ACh receptors are present in the post-junctional membrane of the endplate, in the junctional folds. The nicotinic ACh receptor at the motor endplate has five subunits, two os, (3, 5 and . In addition, a Y subunit instead of an e subunit may be present in the so-called extra-junctional or the fetal receptor. The five subunits are arranged as a cylinder around a central funnel-shaped pore, the ion channel. The two a subunits each carry a recognition site which binds nicotinic agonists such as ACh and antagonists such as the neuromuscular blocking agents. Whilst ACh must bind to both subunits to produce an effect, it is sufficient for... 

Schematic representation of the neuromuscular junction. ACh, acetylcholine AChE, acetylcholinesterase JF, junctional folds M, mitochondrion V, transmitter vesicle.

Schematic representation of the neuromuscular junction. (V, transmitter vesicle M, mitochondrion ACh, acetylcholine AChE, acetylcholinesterase JF, junctional folds.) (Reproduced, with permission, from Drachman DB Myasthenia gravis. N Engl J Med 1978 298 135.)...

Normal NMJs have a generally polarized nerve terminal with accumulations of40-50 nm small clear vesicles near the presynap-tic membrane and mitochondria located farther away (Fig. 20.8). In mice, the terminal Schwann cell capping the nerve terminal can be difficult to resolve. The postsynaptic membrane has a series of junctional folds invaginating into the muscle fiber. At the mouth (crest) of each fold, the membrane appears electron dense because of the accumulation of AChRs. The synaptic cleft is pronounced and contains a visible basal lamina. 

Fig. 20.8. Neuromuscular junctions analyzed by transmission electron microscopy. (A) In wild-type mice, the motor nerve terminal (MN) is depressed into the muscle fiber surface. The terminal is polarized, with small clear vesicles near the presynaptic membrane and mitochondria in the more proximal portion of the terminal. The postsynaptic membrane has deep convolutions (junctional folds, JF) and the membrane near the tops of these folds is very electron dense because of the high density of acetylcholine receptors (arrowheads). (B) In some myasthenias where the nerve sprouts but remains in contact with the muscle, terminals with mitochondria and vesicles are observed in the absence of any postsynaptic specialization. Presumably these are sprouting terminals that have not established a functional connection. (C) Partial innervation of postsynaptic sites is evident as elaborate junctional folds in the muscle membrane with no overlying nerve terminal. In these examples, the interpretations were aided by light microscopy examination of other samples as described in Fig. 20.8 in parallel with electron microscopy. The mutation shown in (B, C) is an unpublished ENU-induced allele of agrin.

Pathological deviations include an absence of junctional folds, partial innervation (folds without an overlying nerve terminal), and vacuolated mitochondria. Assessing more subtle defects, such as changes in vesicle number, requires a statistical analysis on many junctions. 

T221F. This is another gain-of-function SCCMS mutation that has been found in two unrelated families and that causes myasthenic symptoms (102). Ultrastructural studies revealed degenerated junctional folds and diffusely thickened end-plate basal lamina, as in other forms of SCCMS. 

Fig. 11.2. Acetylcholine receptors at the neuromuscular junction. A motor nerve terminates in several branches each branch terminates in a bulb-shaped structure called the presynaptic bouton. Each bouton synapses with a region of the muscle fiber containing junctional folds. At the crest of each fold, there is a high concentration of acetylcholine receptors, which are gated ion channels.

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