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PubMed1997

Genetic analysis of postsynaptic differentiation at the vertebrate neuromuscular junction.

As neuromuscular junctions form in vertebrate skeletal muscle, nicotinic acetylcholine receptors (AChRs) become concentrated in the postsynaptic membrane. The nerve directs this redistribution, using multiple signals to regulate AChRs at both transcriptional and post-translational levels. Recent studies in vitro have led to the identification of candidate nerve-derived signaling molecules (such as agrin, ARIA/neuregulin, and calcitonin gene-related peptide) and components of their intramuscular signaling pathways (including dystroglycan, MuSK, erbB kinases, utrophin, and rapsyn). Studies of knock-out mice are now making it possible to test which signals and pathways are responsible for postsynaptic differentiation in vivo.

Agrin↗
PubMed2004

Glial modulation of synaptic transmission at the neuromuscular junction.

The neuromuscular junction (NMJ) is a cholinergic synapse that controls muscle contraction. Glial cells, called perisynaptic Schwann cells, surround nerve terminals at the NMJ. Transmitter release induced by repetitive nerve stimulation, elicit a frequency-dependent activation of G-protein-coupled receptors on perisynaptic Schwann cells and the release of calcium from internal stores. In return, perisynaptic Schwann cells modulate synaptic activity during and following high-frequency stimulation through short-term plasticity. In the present review, we discuss evidence of glial involvement in the short-term plasticity at the NMJ and the potential impact of such modulation on synaptic efficacy.

Animals↗
PubMed2002

Diseases of the neuromuscular junction.

The neuromuscular junction is a prototype synapse and it is also the site of well-characterised autoimmune and hereditary disorders. In the presynaptic terminal, voltage-gated potassium channels and voltage-gated calcium channels are subtly altered in genetic disorders and mutations in the enzyme that synthesises acetylcholine have been demonstrated in a particular form of hereditary myasthenia syndrome. Recent advances have revealed agrin, muscle-specific kinase (MuSK) and rapsyn as important signalling elements in the development and maintainance of the molecular architecture of the postsynaptic membrane. This is proving relevant to seronegative myasthenia gravis, with the discovery of anti-MuSK antibodies, and to a type of congenital myasthenic syndrome, in which acetylcholine receptor deficiency is due to mutations in rapsyn.

Animals↗
PubMedDate not supplied

Postsynaptic signaling of new players at the neuromuscular junction.

The neuromuscular junction (NMJ) represents the most well studied synapse and is widely regarded as structurally and functionally less complicated than neuronal synapses in the brain. Recent studies, however, have identified the localization and function of new signaling molecules at the NMJ. Surprisingly, many synaptic proteins previously identified in the brain are indeed also concentrated on the postsynaptic muscle side of the NMJ. These include the serine/threonine kinase Cdk5, the neurotrophin receptor TrkB, Eph receptors and ephrins, NMDA receptors and nitric oxide synthase, various PDZ-domain scaffold proteins, and beta-amyloid precursor protein. These observations indicate that the molecular composition of NMJ is much more intricate than we originally thought. The potential significance of these new signaling molecules at the NMJ will be discussed.

Animals↗
PubMed2005

Molecular regulation of postsynaptic differentiation at the neuromuscular junction.

The neuromuscular junction (NMJ) is a synapse that develops between a motor neuron and a muscle fiber. A defining feature of NMJ development in vertebrates is the re-distribution of muscle acetylcholine (ACh) receptors (AChRs) following innervation, which generates high-density AChR clusters at the postsynaptic membrane and disperses aneural AChR clusters formed in muscle before innervation. This process in vivo requires MuSK, a muscle-specific receptor tyrosine kinase that triggers AChR re-distribution when activated; rapsyn, a muscle protein that binds and clusters AChRs; agrin, a nerve-secreted heparan-sulfate proteoglycan that activates MuSK; and ACh, a neurotransmitter that stimulates muscle and also disperses aneural AChR clusters. Moreover, in cultured muscle cells, several additional muscle- and nerve-derived molecules induce, mediate or participate in AChR clustering and dispersal. In this review we discuss how regulation of AChR re-distribution by multiple factors ensures aggregation of AChRs exclusively at NMJs.

Animals↗
PubMed1977

Suppression by elevated calcium of black widow spider venom activity at frog neuromuscular junctions.

Frog neuromuscular junctions were treated with both concentrated black widow spider venom (BWSV) and elevated extracellular calcium (5-50 mM). This procedure causes a dramatic increase in the frequency of spontaneous miniature endplate potentials (mepps) which persists for only a few minutes. In contrast, BWSV-induced mepp activity, the venom effect (VE), continues for 20 min-1 h at junctions in elevated calcium Ringer solutions treated with doses of dilute venom or at junctions in normal calcium (1.91 mM) Ringer solution treated with concentrated venom. Following the disappearance of the VE in elevated extracellular calcium, only a few normal amplitude mepps and a few giant amplitude mepps are observed. The disappearance of the VE in these preparations is irreversible and occurs whether exposure to elevated extracellular calcium precedes or follows exposure to BWSV. Electron microscopy indicates that the major structural alterations produced by exposure to concentrated BWSV and 20 mM calcium Ringer solution are the swelling of nerve terminal mitochondria and the clumping of synaptic vesicles, large numbers of which remain in the terminals. Exposure to 20 mM calcium Ringer solution alone produces no ultrastructural modifications in these preparations. These observations can best be explained if one of the effects of BWSV is to increase the permeability of the nerve terminal membrane to calcium. Only doses of concentrated venom can sufficiently elevate intracellular calcium to a concentration at which synaptic vesicles clump together, thus interruping the transmitter release process.

Action Potentials↗
PubMedDate not supplied

Two synaptic vesicle pools, vesicle recruitment and replenishment of pools at the Drosophila neuromuscular junction.

Drosophila neuromuscular junctions ( D NMJs) are malleable and its synaptic strength changes with activities. Mobilization and recruitment of synaptic vesicles (SVs), and replenishment of SV pools in the presynaptic terminal are involved in control of synaptic efficacy. We have studied dynamics of SVs using a fluorescent styryl dye, FM1-43, which is loaded into SVs during endocytosis and released during exocytosis, and identified two SV pools. The exo/endo cycling pool (ECP) is loaded with FM1-43 during low frequency nerve stimulation and releases FM1-43 during exocytosis induced by high K(+). The ECP locates close to release sites in the periphery of presynaptic boutons. The reserve pool (RP) is loaded and unloaded only during high frequency stimulation and resides primarily in the center of boutons. The size of ECP closely correlates with the efficacy of synaptic transmission during low frequency neuronal firing. An increase of cAMP facilitates SV movement from RP to ECP. Post-tetanic potentiation (PTP) correlates well with recruitment of SVs from RP. Neither PTP nor post-tetanic recruitment of SVs from RP occurs in memory mutants that have defects in the cAMP/PKA cascade. Cyotochalasin D slows mobilization of SVs from RP, suggesting involvement of actin filaments in SV movement. During repetitive nerve stimulation the ECP is replenished, while RP replenishment occurs after tetanic stimulation in the absence of external Ca(2+). Mobilization of internal Ca(2+) stores underlies RP replenishment. SV dynamics is involved in synaptic plasticity and D NMJs are suitable for further studies.

Animals↗
PubMed2006

Molecular architecture of the neuromuscular junction.

The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.

Animals↗
PubMed1991

Gap junctional communication during neuromuscular junction formation.

We have tested whether gap junctions form between nerve and muscle during their initial contact, before establishing the chemical synapse. Embryonic Xenopus stage 18-20 myotomes and neural tubes were permeabilized with DMSO to load appropriate reagents, dissociated, and cocultured. When myotomes, loaded with Lucifer yellow, were cocultured with unlabeled neural tube cells, 23% of the neurons contained dye after 24 hr. Affinity-purified gap junction antibodies loaded into myocytes or neurons reduced neuronal labeling significantly to 5%. [3H]uridine nucleotide transfer was observed in both directions between myocytes and neurons. Again gap junction antibodies substantially reduced recipient label. In all cases preimmune IgGs did not reduce transfer. When acetylcholine receptor clustering was examined in cultures containing gap junction antibodies, no difference in the number of neuronally induced AChR clusters was observed. This suggests that the cluster-inducing signal between nerve and muscle does not pass through gap junctions.

Animals↗
PubMed1998

Localization and characterization of nitric oxide synthase at the frog neuromuscular junction.

The frog neuromuscular junction is sensitive to nitric oxide (NO), since exogenously applied NO reduces the release of transmitter b presynaptic terminals and the size of ATP-induced Caoffresponses in perisynaptic Schwann cells. This study aimed at determining whether an NO synthase (NOS) is present at the neuromuscular junction, notably in perisynaptic Schwann cells, the glial cells at this synapse. The NADPH-diaphorase (NADPH-d) histochemical technique revealed the presence of NOS in cell bodies and presumed processes of perisynaptic Schwann cells. Incubation with NOS inhibitors, NG-nitro-L-arginine methyl ester or NG-nitro-L-arginine-acetate abolished the NADPH-d staining. Moreover, L-arginine, the precursor of NO, impeded the blockade by NOS inhibitors, establishing the NOS specificity of NADPH-d staining in frog tissue. The pattern of labelling with a polyclonal antibody against the neuronal form of NOS was similar to the NADPH-d staining, also suggesting the presence of a neuronal NOS in perisynaptic Schwann cells. Using electron microscopy the NOS immunostaining was found at the membrane and occasionally in the cytoplasm of perisynaptic Schwann cells and was not detected in the nerve terminal or muscle. There was no enzymatic or immunocytochemical labelling of NOS 6 days after denervation. It is concluded that NOS is present in frog perisynaptic Schwann cells. The presence of this endogenous NOS suggests that NO may act as a diffusible glial messenger to modulate synaptic activity and synapse formation at the neuromuscular junction.

Acetylcholinesterase↗
PubMed1980

Differential effects of diltiazem on glutamate potentials and excitatory junctional potentials at the crayfish neuromuscular junction.

1. The effects of diltiazem on glutamate potentials and excitatory junctional potentials (e.j.p.s) were investigated in the crayfish neuromuscular junction. 2. When diltiazem (0.3 mM) was added to the perfusion fluid, the ionophoretic glutamate potential was reduced to about half, whereas the peak amplitude of successive e.j.p.s elicited by a train of pulses of 100/sec increased by about 2 times. 3. It was suggested that diltiazem was a non-competitive inhibitor of L-glutamate. The reduction of the response to applied glutamate was not due to the acceleration of desensitization of the glutamate receptor. The rate of recovery from desensitization was delayzed by diltiazem. 4. The increase in amplitude of e.j.p.s caused by diltiazem was due to the increase in membrane resistance. The quantum content and size of extracellular e.j.p.s were not affected by diltiazem. 5. It was substantiated using the micro-electrode technique that the glutamate sensitive area coincided with the neuromuscular junctional area. 6. The pharmacological difference between glutamate potentials and e.j.p.s revealed in the present study is difficult to explain on the glutamate transmitter hypothesis. One explanation worthy to be considered is that there are two pharmacologically different kinds of receptors sensitive to L-glutamate.

Animals↗
PubMed2004

ATP potentiates agrin-induced AChR aggregation in cultured myotubes: activation of RhoA in P2Y1 nucleotide receptor signaling at vertebrate neuromuscular junctions.

At vertebrate neuromuscular junctions, ATP is known to stabilize acetylcholine in the synaptic vesicles and to be co-released with it. We have shown previously that a nucleotide receptor, P2Y(1) receptor, is localized at the nmjs, and we propose that this mediates a trophic role for synaptic ATP there. In cultured myotubes, the activation of P2Y(1) receptors modulated agrin-induced acetylcholine receptor (AChR) aggregation in a potentiation manner. This potentiation effect in agrin-induced AChR aggregation was reduced by antagonizing the P2Y(1) receptors. The guanosine triphosphatase RhoA was shown to be responsible for this P2Y(1)-potentiated effect. The localization of RhoA in rat and chicken skeletal muscles was restricted at the neuromuscular junctions. Application of P2Y(1) agonists in cultured myotubes induced RhoA activation, which showed an additive effect with agrin-induced RhoA activation. Over-expression of dominant-negative mutant of RhoA in cultured myotubes diminished the agrin-induced AChR aggregation, as well as the potentiation effect of P2Y(1)-specific agonist. Application of UTP in the cultures also triggered similar responses as did 2-methylthioadenosine 5'-diphosphate, suggesting the involvement of other subtypes of P2Y receptors. These results demonstrate that RhoA could serve as a downstream mediator of signaling mediated by P2Y(1) receptor and agrin, which therefore synergizes the effects of the two neuron-derived trophic factors in modulating the formation and/or maintenance of post-synaptic apparatus at the neuromuscular junctions.

Adenosine Triphosphate↗
PubMed1983

Extracellular excitatory junctional current at the crayfish neuromuscular junction.

The nature of the falling phase of the synaptic current was studied in more detail at the crayfish neuromuscular junction and fundamental data relating to focally recorded excitatory junctional potentials (e.j.p.s) was complemented. The decay of extracellular e.j.p.s at the crayfish neuromuscular junction was almost exponential. The decay time constant of extracellular e.j.p.s varied considerably from one e.j.p. to another, the mean of the decay time constant being about 1 ms at the normal resting potential at a bath temperature of 22 degrees C. There was no detectable correlation between the decay time constant and the amplitude of extracellular e.j.p.s which were induced by a single stimulation of the excitatory axon. Prolonged application of glutamate hardly affected the decay time constant of extracellular e.j.p.s. The significance of the study on the crayfish neuromuscular system was discussed.

Action Potentials↗
PubMed1984

Different quantal responses within single frog neuromuscular junctions.

At frog neuromuscular junctions spontaneous miniature end-plate potentials (m.e.p.p.s) were recorded from several isolated spots within single synapses. This was done by consecutively placing an extracellular glass micro-electrode (focal electrode) at different recording sites, while the intracellular electrode remained in one place. After each set of recordings, muscles were stained to reveal both axon terminals and cholinesterase (ChE) such that the exact position of each recording site could be determined. In many nerve terminal branches a similar quantum size was found at several different spots. In other instances, however, mean quantum amplitudes varied by 10-60% at different spots along the same terminal branches. As a control, individual spots were recorded from repeatedly after repositioning the focal electrode. In these recordings mean m.e.p.p. amplitude varied by only 5-10%. It is concluded that quantum size within a single junction is similar at many spots, but deviates markedly at others. Correlation of this variation with the stained preparations suggested that spots where quanta significantly larger or smaller than normal were recorded were either at ChE rings or at the distal ends of nerve branches, respectively; at different nerve terminal branches within the same junction, quantum amplitudes were similar in many cases but deviated in others. The results are consistent with ultrastructural evidence that frog neuromuscular junctions are non-homogeneous structures which undergo continual remodelling.

Action Potentials↗
PubMed1999

Aggregates of acetylcholine receptors are not observed under anti-agrin staining schwann cell processes at the frog neuromuscular junction.

The frog neuromuscular junction offers a unique structure in which to observe fine details in the relationship between the motor neuron, muscle, and Schwann cell, which together comprise the neuromuscular junction. Schwann cell processes that extended from the synapse stained positively with anti-agrin antibodies. Immunocytochemistry revealed strong anti-agrin staining of the extracellular matrix surrounding the entire Schwann cell and the Schwann cell processes come in close contact with the muscle fiber. Dual-labeling experiments revealed a lack of acetylcholine receptor (AChR) aggregates on the surface of the muscle fiber directly under these anti-agrin-staining Schwann cell processes. The cDNA that codes for the C-terminal portion of agrin in frog (Rana pipiens) was cloned and sequenced. Polymerase chain reaction of frog brain, nerve, and muscle cDNA revealed that like other species, agrin transcripts that contain the B8, B11, or B19 inserts were observed only in brain tissue. Unlike other species, the exact site of the B inserts in frog was slightly altered, with the B insertion site occurring within a codon sequence. Our data are consistent with the hypothesis that Schwann cells produce agrin which lacks inserts at the B region, and that agrin lacking B inserts does not direct the aggregation of AChRs in vivo under physiological conditions and concentrations.

Agrin↗
PubMed1980

Factors that influence regeneration of the neuromuscular junction.

Regeneration of neuromuscular junctions after trauma occurs in an orderly way and relies on communication between nerve and muscle. This paper summarizes evidence that factors which direct the growth and differentiation of both pre- and postsynaptic components of regenerating neuromuscular junctions are associated with the extracellular matrix of muscles.

Acetylcholine↗
PubMed2004

Synaptic vesicle cycling at type-identified diaphragm neuromuscular junctions.

Differences in neuromuscular transmission and neuromuscular junction morphology exist across muscle fiber types. We hypothesized that these fiber-type differences are reflected in the size of the cycling synaptic vesicle pool. Synaptic vesicle cycling at type-identified rat diaphragm neuromuscular junctions was examined by fluorescently labeling presynaptic vesicles with FM4-64. We found that FM4-64 fluorescence uptake was higher at presynaptic terminals of type I/IIa fibers than type IIx/IIb fibers. However, no fiber-type differences in the rate of FM4-64 destaining were found with repetitive nerve stimulation. Synaptic vesicle density at active zones was examined by transmission electron microscopy. In accordance with FM4-64 uptake, synaptic vesicle density was greater at type I/IIa than IIx/IIb fibers. These results demonstrate differences in synaptic vesicle cycling across diaphragm muscle fiber types, which may underlie previously observed differences in neuromuscular transmission across diaphragm muscle fiber types. In the diaphragm, motor units comprising type I and type IIa fibers are most frequently recruited with a duty cycle of approximately 40%. Motor units comprising IIx/IIb fibers are infrequently recruited and only for short durations. The capacity for synaptic vesicle release and cycling at different muscle fiber types matches the functional requirements of these motor units. If the demand for recruitment of motor units comprising IIx/IIb fibers increases, for example, with mechanical loading, there is an increased risk for neuromuscular transmission failure that my relate to the capacity for synaptic vesicle release and cycling. Muscle fiber type-specific adaptations should be considered when examining neuromuscular disorders.

Animals↗