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At least 19 recordsLinked to original sources
PubMed1965

Ultrastructure of somatic muscle cells in Ascaris lumbricoides. II. Intermuscular junctions, neuromuscular junctions, and glycogen stores.

Somatic muscle cells of Ascaris lumbricoides consist of three differently specialized components referred to as the fiber, which contains the contractile apparatus (described previously), the belly, and the arm. The belly is shown to be a sac of glycogen, which is depleted during starvation of the animal. The arm extends to a nerve cord where it establishes a myoneural junction characterized by giant mitochondria and clusters of vesicles in the nerve fibers and by a 500 A neuromuscular gap. The arms, which have been shown to be "electrically interconnected" in the vicinity of the nerve cord, form "tight junctions" with one another in just this region. At high magnification, these junctions can be resolved into several types. In some there is fusion of the outer leaflets of the membranes with formation of an intermediate line. Others resemble septate desmosomes in that a residual extracellular space approximately 20 A in width remains between the membranes, but the outer leaflets are interconnected across the gap. It is suggested that the term "tight junction" encompasses a variety of structures distinguishable only at high magnification and that the different variations are not necessarily equivalent functionally.

Ascaris↗
PubMed1983

Normal variations in presynaptic active zones of frog neuromuscular junctions.

Neuromuscular junctions of frog cutaneous pectoris muscles were examined by the complementary-replica freeze-fracture technique. The large number of active zones revealed in this way permitted quantitation of normal and disrupted zones in control muscles and in muscles deprived of external calcium for periods of up to eight hours. Although some 87% of the active zones examined had the usual appearance of two double rows of intramembrane particles flanking a low ridge, several varieties of disrupted active zones appeared in which the rows were interrupted, dispersed, rotated, or reduced to single rows. The frequency of disruptions was not increased by calcium deprivation. Disorganized active zones at tips of neuromuscular junctions may represent normal remodelling of the junctions.

Animals↗
PubMed1991

On the mechanism of spontaneous recovery of neuromuscular transmission after acetylcholinesterase inhibition in the rat neuromuscular junction.

Neuromuscular transmission shows a significant degree of spontaneous recovery after being impeded by acetylcholinesterase inhibition. Part of this recovery can be ascribed to de novo synthesis of acetylcholinesterase but another part is independent of enzyme activity. To unravel the mechanism underlying this synaptic adaptation to acetylcholinesterase inhibition we have compared a number of electrophysiological parameters in diaphragms taken from animals that were sacrificed within 15 min after a 2 x LD50 dose of the acetylcholinesterase inhibitor diisopropylfluorophosphate and from similarly treated animals killed after being kept alive for 3 h under artificial respiration. We found no differences in the quantal content. There was a significantly smaller degree of endplate potential rundown at tetanic stimulation and the miniature endplate potential amplitude was smaller in the 3-h adapted animals. In addition, the desensitization induced by carbachol appeared to be less in this group. It is likely that these synaptic changes, demonstrating the plasticity of the neuromuscular synapse, are involved in the spontaneous recovery of neuromuscular transmission after acetylcholinesterase inhibition.

Animals↗
PubMed1995

Dynamics of nerve-muscle interaction in developing and mature neuromuscular junctions.

Neuromuscular connections have long served as models of synaptic structure and function. They also provide illuminating insights into the dynamic cell-cell interactions governing synaptogenesis, neuromuscular differentiation, and the maintenance of effective function. This paper reviews recent advances in our understanding of the regulatory and inductive interactions involved in motor axon pathfinding, target recognition, bidirectional control of gene expression during synapse formation, motoneuron cell death, terminal rearrangement, and the ongoing remodeling of synaptic number, structure, and function to adjust to growth and changes in use.

Acetylcholinesterase↗
PubMed1969

Development of the neuromuscular junction. I. Cytological and cytochemical studies on the neuromuscular junction of differentiating muscle in the regenerating limb of the newt Triturus.

Development of the neuromuscular junction on differentiating muscle was investigated in the regenerating limb of the newt Triturus. Motor end-plate formation begins when vesicle-filled axon terminations approach differentiating muscle cells that have reached the stage of a multinucleate cell containing myofibrils. Slight ridges or elevations occur on the muscle surface, and there is an increase in density of the cytoplasm immediately beneath the plasma membrane of the elevation. The axon becomes more closely approximated to the muscle cell and comes to lie in a shallow depression or gutter on the surface of the muscle. The surface ridges increase in length and constrict at their bases to form junctional folds. In the axon terminal, focal accumulations of vesicles are found where the axon contour projects slightly opposite the secondary synaptic clefts. Cholinesterase activity in the developing junctions was demonstrated by the thiolacetic acid-lead nitrate method. Enzymatic activity is not found on intercellular nerve fibers or the muscle surface prior to close approximation of axon endings and muscle. Eserine- and DFP-sensitive activity appears concurrently with morphological differentiation. Activity occurs in membranous tubulovesicles in the sarcoplasm subjacent to the neuromuscular junction and in association with the sarcolemma. The largest reaction deposits occur at the tips of the emerging junctional folds. Smaller and less numerous localizations occur on the axon membrane and within the axoplasm. It is concluded from these studies that the nerve endings have an inductive effect on both the morphological and chemical specializations of the neuromuscular junction.

Animals↗
PubMed1994

Retrograde signaling in the formation and maintenance of the neuromuscular junction.

The neuromuscular junction is characterized by precise alignment between the nerve terminal and the postsynaptic apparatus formed by the muscle fiber. Organization of the neuromuscular junction during embryonic development, growth, and maintenance is coordinated by signals exchanged between motor neurons and their target muscle fibers. Identification of proteins such as agrin, likely to represent neuronal agents that direct the organization of the postsynaptic apparatus, has focused attention on characterization of proteins that mediate retrograde signals that regulate the organization and function of the nerve terminal. The results of these studies implicate a role for both adhesive and diffusible signals in coordinating the development, maturation, and maintenance of the motor nerve terminal. The diversity of molecules identified to date that appear to play a role in these processes implies a considerable level of redundancy in the transduction pathway. However, studies of early nerve-muscle interactions suggest that a common feature of many of these retrograde agents is activation of a protein kinase coupled with an increase in cytosolic Ca2+ concentration. While the molecular signals that regulate growth and maintenance of neuromuscular junctions are less well understood it seems likely that similar adhesive and diffusible factors will be involved.

Animals↗
PubMed1999

Heme oxygenase-2 expression at rat neuromuscular junctions.

The neuromuscular junction is specialized for rapid transmission of electrical signals. Nitric oxide synthase (NOS) is concentrated at the junction, and NO modulates transmission and could influence signaling pathways. Increasing evidence suggests that carbon monoxide (CO) serves as a neurotransmitter, and heme oxygenase (HO), the enzyme that catalyzes the formation of CO, is often colocalized with NOS. Immunoreactivity for HO-2 was present at rat neuromuscular junctions of leg muscles and persisted in denervated muscle indicating the localization of the enzyme to the postsynaptic surface. In contrast, HO-2 immunoreactivity was absent from the en grappe and orbital en plaque endplates of extraocular muscle (EOM), while only the global en plaque endplates possessed HO-2 immunoreactivity. The difference between EOM and leg endplates may arise from EOM's unique physiology. The presence of HO-2 at neuromuscular junctions suggests CO could serve as a pre- and post-synaptic messenger.

Animals↗
PubMed1996

Anti-agrin staining is absent at abandoned synaptic sites of frog neuromuscular junctions.

The neuromuscular junction is a plastic structure and is constantly undergoing changes as the nerve terminals that innervate the muscle fiber extend and retract their processes. In vivo observations on developing mouse neuromuscular junctions revealed that prior to the retraction of a nerve terminal the acetylcholine receptors (AChRs) under that nerve terminal disperse. Agrin is a protein released by nerve terminals that binds to synaptic basal lamina and directs the aggregation of AChRs and acetylcholinesterase (AChE) in and on the surface of the myotube. Thus, if the AChRs under a nerve terminal disperse, then the cellular signaling mechanism by which agrin maintains the aggregation of those AChRs, must have been disrupted. Two possibilities that could lead to the disruption of the agrin induced aggregation are that agrin is present at the synaptic basal lamina but is unable to direct the aggregation of AChRs, or that agrin has been removed from the synaptic basal lamina. Thus, if agrin were blocked, one would expect to see anti-agrin staining at abandoned synaptic sites; whereas if agrin were removed, anti-agrin staining would be absent at abandoned synaptic sites. We find that anti-agrin staining and alpha-bungarotoxin staining are absent at abandoned synaptic sites. Further, in vivo observations of retracting nerve terminals confirm that agrin is removed from the synaptic basal lamina within 7 days. Thus, while agrin will remain bound to synaptic basal lamina for months following denervation, it is removed within days following synaptic retraction.

Acetylcholinesterase↗
PubMedDate not supplied

Rabies virus infection of myotubes and neurons as elements of the neuromuscular junction.

The neuromuscular junction represents a site of transit for both fixed and street rabies viruses. Infection of cultured rat myotubes by fixed rabies virus was found to be restrictive, and although fluorescence observations showed that cells were infected, there were no infectious virus particles in the supernatant of infected myotubes. In contrast, infection of myotubes with street rabies virus produced infectious virus particles, and kinetic studies noted a growth cycle in these cells. Neurons derived from the rat spinal cord or from dorsal root ganglia were 10-100-fold more susceptible to infection with fixed rabies challenge virus strain (CVS) than were the myotubes, a finding that confirms the basically neurotropic nature of rabies virus. The abortive infection of CVS rabies in muscle cells may be one possible mechanism by which virus persists at the site of inoculation. In addition, competition-binding experiments show that alpha-bungarotoxin at 10(-5)-10(-7) M inhibits rabies virus infection of myotubes, a finding that suggests the involvement of low-affinity nicotinic acetylcholine receptors for rabies virus. Sialic acid was shown to be necessary for the attachment of rabies virus to the myotubes, a requirement confirming earlier data for other cell types. These data confirm observations in vivo. Infection of these cells in primary culture, which represent the natural target for rabies virus, mimics the situation in vivo. Such a model permits further investigation of virus-cell interactions at the neuromuscular junction.

Animals↗
PubMed1987

Coated vesicles and pits during enhanced quantal release of acetylcholine at the neuromuscular junction.

Frog neuromuscular junctions were stimulated by different methods to secrete quanta of ACh, and the attendant changes in the ultrastructure of the nerve terminal were assessed by morphometric analysis of electron micrographs. Secretion was stimulated by electrical stimulation at 2 Hz or by application of the secretagogues, lanthanum, ouabain or black widow spider venom, either in the presence or in the absence of extracellular Ca2+. The numbers of synaptic vesicles, coated vesicles and coated pits, and the length of axolemma and area of axoplasm were measured on the micrographs. There was a significant increase (about threefold) in the total number of coated structures (vesicles plus pits) per micron2 of axoplasm, but the fractional increase in the number of coated pits exceeded the fractional increase in the number of coated vesicles. These increases were positively correlated with the increase in the length of axolemma per unit area and negatively correlated with the changes in concentration of synaptic vesicles, suggesting that they were due to the increases in the surface area of the terminal that accompany a loss of vesicles. However, the increase in the concentration of coated structures was not related to the number of quanta secreted or to the estimated number of vesicles recycled. The lack of correspondence between the fractional increases in the coated pits and coated vesicles and the poor correlation between the numbers of these structures and the overall parameters of the secretory process suggest that, in contrast to the situation in other secretory systems, coated pits and coated vesicles may not play a crucial role in maintaining the functional population of synaptic vesicles at rapidly secreting neuromuscular junctions.

Acetylcholine↗
PubMed1980

Structure of developing frog neuromuscular junctions.

Developing neuromuscular junctions in the cutaneous pectoris muscle from tadpoles and and postmetamorphic frogs were studied in the light microscope. Presynaptic nerve terminals and postsynaptic acetylcholinesterase (AChE) activity simultaneously demonstrated at these developing junctions using the NBT-AChE method. The earliest nerve contacts studied were small enlargements at the ends of unmyelinated axons. As development progressed, single nerve contacts, often with growth cones, grew in length, generally parallel to the long axis of the myotube. Further endplate maturation was characterized by individual terminal processes developing secondary and tertiary branches, ultimately leading to highly complex terminal arborizations. The initial synaptic contact at developing neuromuscular junctions was made by a single axon, but with further development these same synaptic sites became multiply innervated. The occurrence of multiple innervation was a transient phenomena; the multiple synaptic inputs were eliminated during further maturation. The time course of synapse elimination was protracted, with some multiple innervation even persisting in relatively large adult frogs. The first nerve contacts were generally devoid of observable endplate AChE activity. Early appearance of AChE activity was sometimes graded and in some cases portions of the nerve terminal processes were associated with AChE while other regions of the same terminal arborization were not.

Acetylcholinesterase↗
PubMed2004

Intracellular expression profiling by laser capture microdissection: three novel components of the neuromuscular junction.

The neuromuscular junction (NMJ) is a regionally specialized area of myofibers defined, in part, by specific gene expression from underlying myonuclei. We sought to obtain a more complete picture of the mRNA transcripts and proteins playing a role in NMJ formation and maintenance using laser capture microdissection (LCM) and to define expression profiles of the nuclear domain at the NMJ. NMJs (800) were isolated from normal mouse tibialis anterior muscle by LCM, with an equal amount of adjacent non-NMJ regions isolated. Many known components of the NMJ were found significantly differentially expressed. Three differentially expressed potential novel components of the NMJ were chosen for further study, and each was validated by immunostaining with and without blocking peptides (3/3), quantitative RT-PCR (3/3), and in situ hybridization (1/3). The three genes validated were dual-specificity phosphatase-6 (DUSP6), ribosomal receptor-binding protein-1 (RRBP1), and vacuolar protein sorting-26 (VPS26). Query of each of these novel components in a 27-time point in vivo muscle regeneration series showed expression commensurate with previously known NMJ markers (nestin, alpha-ACh receptor). Understanding and discovering elements responsible for the integrity and function of NMJs is relevant to understanding neuromuscular diseases such as spinal muscular atrophy. Our LCM-based mRNA expression profiling provided us with new means of identification of specific genes potentially responsible for NMJ stability and function and new candidates for involvement in disease pathogenesis.

Acetylcholinesterase↗
PubMed2005

Use of repetitive nerve stimulation in the evaluation of neuromuscular junction disorders.

Neuromuscular junction (NMJ) disorders are characterized by fuctuating muscle weakness. Acquired myasthenia gravis is the most common NMJ disorder with an overall prevalence in United States estimated at 60,000. Depending on the site of neuromuscular transmission failure, NMJ disorders have been classified as: (1) presynaptic (e.g., Lambert-Eaton myasthenic syndrome), (2) synaptic (e.g., cholinesterase inhibitor toxicity), and (3) post-synaptic (e.g., myasthenia gravis). Electrodiagnostic techniques used for investigation of NMJ disorders include repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG). Recent literature widely explores the use of SFEMG in the diagnosis and monitoring of myasthenia gravis, but this technique has a lesser role in the daily clinical practice outside of academic institutions. RNS is not as sensitive as SFEMG, but it is the most widely used electrodiagnostic method in the evaluation of suspected neuromuscular transmission disorders. RNS is technically easier and does not require special technical training and skill as SFEMG. Repetitive nerve stimulation was utilized first by Jolly in 1895 using an electrical drum and faradic tetanization to demonstrate a "myasthenic reaction" (weakening muscle contractions). In 1941, decremental response following the repetitive nerve stimulation was described by Harvey and Masland. While the technology has improved tremendously since then, the RNS testing is still based on supramaximal repetitive nerve stimulation and the measurement of decremental (or incremental) responses.

Electric Stimulation↗
PubMed1978

Competitive antagonism between calcium and antibiotics at the neuromuscular junction.

The neuromuscular blockade produced by the amino-glycosidic-aminocyclitolic antibiotics streptomycin and kanamycin and its reversal by calcium was quantitatively studied in the isolated phrenic nerve-diaphragm preparation of the rat. The low dose-response curves obtained presenting no significant deviation from parallelism are highly suggestive of a competitive type of antagonism between those substances. The streptidinic moiety of streptomycin showed the same properties as the original antibiotic. Streptomycin and kanamycin decreased the amplitude of intracellularly recorded e.p.p.'s of the toad sartorius muscle in a manner quite similar to that described for magnesium ions which suggests an interference of the antibiotics with the cooperative interaction of calcium ions with specific receptive sites at the presynaptic membrane of the neuromuscular junction.

Animals↗
PubMed1985

Activity and synapse elimination at the neuromuscular junction.

The neuromuscular junction undergoes a loss of synaptic connections during early development. This loss converts the innervation of each muscle fiber from polyneuronal to single. During this change the number of motor neurons remains constant but the number of muscle fibers innervated by each motor neuron is reduced. Evidence indicates that a local competition among the inputs on each muscle fiber determines which inputs are eliminated. The role of synapse elimination in the development of neuromuscular circuits, other than ensuring a single innervation of each fiber, is unclear. Most evidence suggests that the elimination plays little or no role in correcting for errant connections. Rather, it seems that connections are initially highly specific, in terms of both which motor neurons connect to which muscles and which neurons connect to which particular fibers within these muscles. A number of attempts have been made to determine the importance of neuromuscular activity during early development for this rearrangement of synaptic connections. Experiments reducing neuromuscular activity by muscle tenotomy, deafferentation and spinal cord section, block of nerve impulse conduction with tetrodotoxin, and the use of postsynaptic and presynaptic blocking agents have all shown that normal activity is required for normal synapse elimination. Most experiments in which complete muscle paralysis has been achieved show that activity may be essential for the occurrence of synapse elimination. Furthermore, experiments in which neuromuscular activity has been augmented by external stimulation show that synapse elimination is accelerated. A plausible hypothesis to explain the activity dependence of neuromuscular synapse elimination is that a neuromuscular trophic agent is produced by the muscle fibers and that this production is controlled by muscle-fiber activity. The terminals on each fiber compete for the substance produced by that fiber. Inactive fibers produce large quantities of this substance; on the other hand, muscle activity suppresses the level of synthesis of this agent to the point where only a single synaptic terminal can be maintained. Inactive muscle fibers would be expected to be able to maintain more nerve terminals. The attractiveness of this scheme is that it provides a simple feedback mechanism to ensure that each fiber retains a single effective input.

Animals↗
PubMed1988

Characteristics of spontaneous miniature and subminiature end-plate currents at the mouse neuromuscular junction.

1. Neuromuscular junctions of the mouse diaphragm were voltage clamped with a two-electrode voltage clamp in order to evaluate time characteristics of miniature end-plate currents (MEPCs). 2. The MEPCs fell into two amplitude classes: a larger class with an overall bell-shaped distribution (bell MEPCs) and a smaller class which forms a right-hand skew distribution (skew MEPCs). The mean MEPC amplitudes varied greatly because of the large range in the ratio of skew to bell MEPCs. This variation was greatest in neonate mice. 3. Rise time and time-to-peak were the same for MEPCs of the skew and bell classes. The MEPCs of both classes in neonate and adult mice had the same ratio of area (charge) over amplitude and the same time constant of decay. The absolute values changed with maturation (at 30 degrees C the ratio of area/amplitude was 4.5 +/- 0.8 ms in the newborn and 1.2 +/- 0.05 ms in the adult; the time constant of decay was 5.6 +/- 1.2 ms in the newborn and 0.8 +/- 0.05 ms in the adult). 4. Atypical MEPCs were found at all junctions. These had slow rising and falling phases, notches on the rising phases or a step the size of the sub-MEPC class. The number of atypical MEPCs increased during the experiment. 5. The data suggest that both skew and bell MEPC classes are released from the same presynaptic region and are generated by the same postsynaptic mechanism.

Animals↗
PubMed2006

MuSK signaling at the neuromuscular junction.

The neuromuscular junction (NMJ) is a peripheral cholinergic synapse that conveys signals from motor neurons to muscle cells (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). The formation of the NMJ requires communication between motoneurons and muscle fibers. Three molecules are essential for NMJ formation: agrin, MuSK, and rapsyn. MuSK appears to be involved in every aspect of NMJ development and maintenance. The paper reviews agrin-MuSK cascades and its potential cross talk with Wnt signaling pathways.

Agrin↗