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PubMed2004

MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction.

At the neuromuscular junction, acetylcholinesterase (AChE) is mainly present as asymmetric forms in which tetramers of catalytic subunits are associated to a specific collagen, collagen Q (ColQ). The accumulation of the enzyme in the synaptic basal lamina strictly relies on ColQ. This has been shown to be mediated by interaction between ColQ and perlecan, which itself binds dystroglycan. Here, using transfected mutants of ColQ in a ColQ-deficient muscle cell line or COS-7 cells, we report that ColQ clusterizes through a more complex mechanism. This process requires two heparin-binding sites contained in the collagen domain as well as the COOH terminus of ColQ. Cross-linking and immunoprecipitation experiments in Torpedo postsynaptic membranes together with transfection experiments with muscle-specific kinase (MuSK) constructs in MuSK-deficient myotubes or COS-7 cells provide the first evidence that ColQ binds MuSK. Together, our data suggest that a ternary complex containing ColQ, perlecan, and MuSK is required for AChE clustering and support the notion that MuSK dictates AChE synaptic localization at the neuromuscular junction.

Acetylcholinesterase↗

PubMed2006

Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction.

At the neuromuscular junction, ATP is co-released with the neurotransmitter acetylcholine (ACh) and once in the synaptic space, it is degraded to the presynaptically active metabolite adenosine. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of extracellular ATP (100 muM) and the slowly hydrolysable ATP analog 5'-adenylylimidodiphosphate lithium (betagamma-imido ATP) (30 muM) on miniature end-plate potential (MEPP) frequency. We found that application of ATP and betagamma-imido ATP decreased spontaneous secretion by 45.3% and 55.9% respectively. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) adenosine receptor antagonist and alpha,beta-methylene ADP sodium salt (alphabeta-MeADP), which is an inhibitor of ecto-5'-nucleotidase, did not prevent the inhibitory effect of ATP, demonstrating that the nucleotide is able to modulate spontaneous ACh release through a mechanism independent of the action of adenosine. Blockade of Ca(2+) channels by both, Cd(2+) or the combined application of nitrendipine and omega-conotoxin GVIA (omega-CgTx) (L-type and N-type Ca(2+) channel antagonists, respectively) prevented the effect of betagamma-imido ATP, indicating that the nucleotide modulates Ca(2+) influx through the voltage-dependent Ca(2+) channels related to spontaneous secretion. betagamma-Imido ATP-induced modulation was antagonized by the non-specific P2 receptor antagonist suramin and the P2Y receptor antagonist 1-amino-4-[[4-[[4-chloro-6-[[3(or4)-sulfophenyl] amino]-1,3,5-triazin-2-yl]amino]-3-sulfophenyl] amino]-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic acid (reactive blue-2), but not by pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt (PPADS), which has a preferential antagonist effect on P2X receptors. Pertussis toxin and N-ethylmaleimide (NEM), which are blockers of G(i/o) proteins, prevented the action of the nucleotide, suggesting that the effect is mediated by P2Y receptors coupled to G(i/o) proteins. The protein kinase C (PKC) antagonist chelerythrine and the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) occluded the effect of betagamma-imido ATP, while the protein kinase A (PKA) antagonist KT-5720 and the inhibitor of the calcium/calmodulin-dependent protein kinase II (CAMKII) KN-62 failed to do so. betagamma-Imido ATP did not affect 10, 15 and 20 mM K(+)-evoked release and application of reactive blue-2 before incubation in high K(+) induced a higher asynchronous secretion. Thus, our results show that at mammalian neuromuscular junctions, ATP induces presynaptic inhibition of spontaneous ACh release due to the modulation of Ca(2+) channels related to tonic secretion through the activation of P2Y receptors coupled to G(i/o) proteins. We also demonstrated that at increasing degrees of membrane depolarization evoked by K(+), endogenously released ATP induces presynaptic inhibition as a means of preventing excessive neurotransmitter secretion.

Acetylcholine↗

PubMed1983

Ultrastructural abnormalities of muscle and neuromuscular junction differentiation in a bovine congenital neuromuscular disease.

The syndrome of arthrogryposis and palatoschisis (SAP), an inherited syndrome of muscular hypotonia in Charolais cattle, was used as an experimental model to study neuromuscular differentiation. The ultrastructural development of muscle, peripheral nerve, and neuromuscular junctions was studied to determine the sequence of events preceding hypotrophic changes in the skeletal muscles of affected calves at birth. Dorsiflexion of the metatarsophalangeal joints in the hindlimbs occurred in fetuses older than 3 months of age, but hypotrophic changes in skeletal muscle, manifested as small fibers scattered among larger and occasional degenerating fibers, was not apparent until late in gestation, affecting 8-month-old fetuses and neonatal calves. Electron microscope and enzyme histochemistry studies disclosed differentiation of skeletal muscle into fiber types which is consistent with changes expected from disuse and does not indicate a primary myopathic abnormality. Abnormal differentiation of neuromuscular junctions (NMJ), composed of several separated axonal endings terminating in shallow synaptic gutters, indicated impaired maturation of the synapse. The earliest indication of abnormal NMJ was observed in a 5-month-old SAP fetus. The clinical signs and pathologic changes found in the neuromuscular junction and skeletal muscle of SAP fetuses are consistent with an embryologic defect occurring during development of the central nervous system (CNS) that affects the integrated function of the motor neurons to the limbs. However, diversification of myofibers by histochemistry and ultrastructural parameters is evidence that the intrinsic physiologic properties of spinal motor neurons were retained.

Animals↗

PubMed1979

Comparison of pre-junctional alpha-adrenoceptors at the neuromuscular junction with vascular post-junctional alpha-receptors in cat skeletal muscle.

1 Activation of pre-junctional alpha-adrenoceptors at the skeletal neuromuscular junction enhances acetylcholine release whereas activation of such receptors at autonomic nerve endings inhibits transmitter output. In the present study the characteristics of pre-junctional alpha-adrenoceptors at motor nerve terminals have been compared with post-junctional (vascular) alpha-adrenoceptors in the cat hind limb.2 Reversal of partial (+)-tubocurarine blockade of contractions of the tibialis anterior muscle was used to monitor pre-junctional activity and increases in hindlimb vascular resistance to assess post-junctional actions at alpha-adrenoceptors.3 Responses to intra-arterial injections of noradrenaline, adrenaline, phenylephrine, oxymetazoline, methoxamine and clonidine were monitored. Dose-response lines for all the compounds except clonidine were parallel. The latter agent produced only weak and inconsistent effects.4 Ratios of the doses of the agents required to produce pre- and post-junctional effects indicated that oxymetazoline and adrenaline possessed some preferential activity at post-junctional sites, whereas the remaining agents were non-selective in their actions. If dose-ratios with respect to noradrenaline were compared at the two sites none of the compounds possessed a marked degree of selectivity.5 In the presence of phentolamine or tolazoline, dose-response curves to the pre- and post-junctional effects of phenylephrine were shifted to a similar extent. Thymoxamine showed preferential activity as a pre-junctional alpha-receptor antagonist.6 In comparing the results of this study with those of other authors, it is apparent that there are marked differences in the characteristics of pre-junctional alpha-receptors at the skeletal neuromuscular junction and at autonomic nerve endings. The pre- and post-junctional alpha-receptors in skeletal muscle show less divergence.

Animals↗

PubMed1987

Forskolin counteracts the effects of the organophosphate soman at the neuromuscular junction.

When neuromuscular transmission had been blocked using an organophosphate, function could be restored by treatment of the muscle with forskolin which increases the rate of desensitization of the nicotinic acetylcholine receptor. This suggests that excess post-synaptic depolarization due to acetylcholinesterase inhibition might be reversed by procedures which promote receptor desensitization.

Action Potentials↗

PubMed1995

Involvement of extracellular matrix in acetylcholine receptor epsilon-subunit gene expression at the rat neuromuscular junction.

During neuromuscular development, the nerve induces the expression of acetylcholine receptor (AChR) epsilon-subunit gene selectively in synaptic myonuclei. Here we show that even after elimination of neural effects by denervation, synaptic expression of epsilon-subunit transcripts is maintained for > 4 months. In contrast, after damage of the extracellular matrix (ECM) by treatment with proteolytic enzymes, epsilon-subunit mRNA is significantly reduced within less than 1 day, indicating a role of ECM in the regulation of AChR subunit transcripts at the synapse.

Animals↗

PubMed1992

A novel peptide toxin from Trimeresurus wagleri acts pre- and post-synaptically to block transmission at the rat neuromuscular junction.

The neuromuscular effects of a peptide toxin (peptide I) from venom of Trimeresurus wagleri were investigated using the rat extensor digitorum longus muscle/peroneal nerve preparation. Sub-micromolar concentrations depressed endplate currents (EPCs) produced in response to nerve stimulation. Since quantal content of EPCs was not altered, it appears that the site of action is post-synaptic. However, higher concentrations (1.4-2.9 microM) also inhibited spontaneous release of transmitter. Nerve stimulation in the presence of peptide I caused 'rundown' of EPC amplitude, evidence that the peptide acts pre-synaptically to interfere with transmitter release. Recovery from this effect occurred within 3-5 min. of washing, but EPC amplitude took 20-30 min. to recover. The dual action of this peptide makes it unusual amongst naturally-occurring toxins, and these data suggest that further investigation of the peptide (and its analogues) could yield new information about neurotransmitter release.

Animals↗

PubMed1987

Phylogenetic polymorphism on lectin binding to junctional and non-junctional basal lamina at the vertebrate neuromuscular junction.

The histochemical binding of seven fluoreceinated lectins was comparatively studied in muscular tissue from twenty three different animal species including mammalians, amphibians, avians and fishes. Special interest was taken in the exploration of the differential lectin-binding properties at the neuromuscular synapse. Binding to synaptic sites was demonstrated using lectins that recognizes N-acetylgalactosamine and among of them, Dolichus biflorus agglutinin (DBA), was the most specific. Nevertheless, DBA fails to stain endplates in the muscle from most of the avians and the fishes (including the Torpedo electric organ) indicating that a polymorphic distribution of glycoconjugates exist at the vertebrate neuromuscular junction. Other lectins such as Concanavalin A (ConA) or Wheat germ agglutinin (WGA), share a similar staining properties in all animals that we examined making an intense label over the complete muscle surface. Although the species-related polymorphism on lectin binding does not reveal a clear relationship with the evolutionary tree, they give an evidence on the chemical heterogeneity of molecules specifically concentrated at the neuromuscular junction.

Animals↗

PubMedDate not supplied

Structural determinants of the reliability of synaptic transmission at the vertebrate neuromuscular junction.

The reliability of neuromuscular transmission depends on the size and molecular organization of the neuromuscular junction. Comparative studies show that the quantal release per unit area is similar at neuromuscular junctions in a number of species in spite of wide variation in synaptic area. They also show an inverse relationship between the size of the nerve terminal and the extent of postsynaptic folding. Evidence is presented supporting the view that the folds, and the voltage-gated sodium channels present in them, effectively amplify synaptic currents. How are the size and molecular organization of the neuromuscular junction determined? Studies with botulinum toxin, including our new work on humans, reveal striking "adaptive plasticity" of the nerve terminal. However, the links between synaptic size and effective transmission remain unclear. On the postsynaptic side, we have shown that mRNA encoding sodium channels is concentrated at the adult junction. During development, mRNA accumulates just before the protein it encodes. Throughout development the sodium channels are associated with ankyrinG and both proteins are initially excluded from the junctional acetylcholine receptor cluster, possibly accounting for the formation of the boundary between the domains occupied by the two key postsynaptic ion channels. These findings have important clinical implications. Reduced transmitter release may result from small nerve terminals as much as from defective release. Abnormal folding is likely to reduce the reliability of transmission. A better understanding of how the structural features that influence the reliability of the neuromuscular transmission are controlled should be of general interest to neuroscientists and of use to clinicians.

Animals↗

PubMed1992

Focal, extracellular recording of slow miniature junctional potentials at the mouse neuromuscular junction.

Miniature endplate potentials (MEPPs) with slow rising phase can be attributed either to burst of transmitter releases or to distortion of conduction from remote releasing sites. The spontaneous activity of neuromuscular junctions recorded extracellularly at mouse diaphragms using sharp electrodes was analyzed to test these two hypotheses. The miniature junctional potentials (MEJPs) frequencies observed intracellularly as compared to MEPP frequency measured intracellularly in controls indicate that most events recorded extracellularly are induced by the presence of the electrode. All types of MEPPs (bell-MEPPs, skew-MEPPs, slow-, and giant MEPPs) previously described with intracellular recording methods (Vautrin and Kriebel, Neuroscience 41:71-88, 1991) were observed extracellularly and showed similar characteristics. This means that the presynaptic and postsynaptic zones that generate these synaptic events are restricted within areas of a few micrometers squared of synaptic contact. Long rise times of extracellularly recorded synaptic spontaneous events may be explained by multiple transmitter releases at intervals shorter than the rise time of individual events, which postsynaptic responses fuse into a single peak.

Animals↗

PubMed1985

Inhibitory actions of tuberostemonine on the excitatory transmission at the crayfish neuromuscular junction.

At the crayfish neuromuscular junction, tuberostemonine, an alkaloid from Stemona japonica, reduced the amplitude of both the excitatory junctional potential (e.j.p.) and the glutamate response in a dose-dependent manner at concentrations above 0.1 mM. Tuberostemonine acted presynaptically on the crayfish neuromuscular junction to reduce a quantal content of extracellularly recorded e.j.p.s, and postsynaptically to reduce their unit size. The decay of the excitatory synaptic current was accelerated by tuberostemonine. The gradual decline of the successive glutamate currents induced by a train was facilitated by the presence of tuberostemonine even in the muscle fibre pre-treated with concanavalin A. The rate of recovery from the refractory form of the glutamate receptor to the free reactive one was slightly affected by tuberostemonine when it was determined by using a paired pulse method. The inhibitory action of tuberostemonine on glutamate responses was voltage-dependent and hyperpolarization increased the drug action. These results indicate that tuberostemonine acts in part as an open-channel blocker at the crayfish neuromuscular junction.

Alkaloids↗

PubMed1980

A transverse tubular system and neuromuscular junctions in a molluscan unstriated muscle.

The buccal mass retractor muscles of Philine aperta are unusual in possessing a system of transverse tubules in what are in other respects typical unstriated muscle fibres. The tubules are formed from invaginations of the sarcolemma that penetrate up to 9 micron radially into the fibre. There is some indication that the tubules are zoned at certain points along the fibre. Physiologically, the outer membrane of the muscle fibre does not support an action potential, and the fibre contracts by summation of small twitches in response to individual excitatory junction potentials. Neuromuscular junctions occur in shallow grooves along the surface of the fibres. They contain 3 types of vesicles; clear, intermediate and dense-cored. A scheme suggesting how striated muscle may be derived from the unstriated condition is described.

Animals↗

PubMed1970

Habituation: occurrence at a neuromuscular junction.

At the neuromuscular junctions between the motor giant axon and fast flexor muscle fibers in crayfish, stimulation at frequencies of one per minute produces a large decline in the amplitude of excitatory junctional potentials. Recovery (dishabituation) can be brought about by increases in stimulus frequency, which trigger a potentiation process; at still higher frequencies, a second form of depression intervenes. The last process appears to be due to depletion of transmitter; the first probably depends instead upon electrical changes in presynaptic terminals. Because of the interactions between the three processes, the junctions display the properties of habituation and dishabituation usually associated with complex central nervous networks.

Animals↗

PubMed1986

Novel antigens at the neuromuscular junction.

Three novel components of neuromuscular junctions have been identified by use of monoclonal antibodies (McAb) against glycoproteins obtained from a mouse neuroblastoma X human dorsal root ganglion cell hybrid line. Antigen distribution was assessed by fluorescent immunohistochemistry on frozen sections of human intercostal muscle counterstained with labeled alpha-bungarotoxin to identify neuromuscular junctions. Antigen SOS 6 stained exclusively in the neuromuscular junction, whereas antigens SOS 5 and SOS 13 were highly enriched in the junction but also stained extrasynaptic regions. These antigens can be distinguished from previously described components of the neuromuscular junction by their molecular weights, insensitivity to collagenase treatment, and solubility in 0.1% Triton X-100. Indirect evidence suggests that these species-specific antigens are located in the postsynaptic muscle membrane, but location in the junctional basal lamina or subsarcolemmal region cannot be excluded.

Acetylcholinesterase↗

PubMed1993

Effects of stonefish (Synanceia trachynis) venom on murine and frog neuromuscular junctions.

The neuromuscular toxicity of stonefish (Synanceia trachynis) venom was characterized by electrophysiological and electron microscopic examination of isolated murine and frog nerve-skeletal muscle preparations exposed to various concentrations of venom. Low concentrations of venom (2.5-10 micrograms/ml) acted presynaptically by causing release and depletion of neurotransmitter from the nerve terminal. The response was Na+ channel-independent (resistant to tetrodotoxin), required the presence of either Ca2+ or Mg2+, and was observed with botulinum neurotoxin-paralyzed nerve-muscle preparations. Higher concentrations of venom (100-300 micrograms/ml) acted postsynaptically and presynaptically. They caused irreversible depolarization of muscle cells and microscopically observable muscle and nerve damage. We conclude that the previously observed neuromuscular toxicity of stonefish venom is a consequence of the venom's dose-dependent, presynaptic and postsynaptic actions at the myoneural junction.

Acetylcholine↗

PubMed2002

Angiotensin 1-7 increases quantal content and facilitation at the frog neuromuscular junction.

At the neuromuscular junction, several endogenous substances have been shown to act presynaptically to modify transmitter release. Here we show that angiotensin 1-7, a vasoactive peptide of the renin-angiotensin system, increased quantal content in a dose-dependent manner, with a maximal increase of 78% at 250 nM. At the same dose, angiotensin 1-7 increased paired pulse facilitation by 70%. This is the first report of angiotensin 1-7 altering a cholinergic synapse.

Acetylcholine↗

PubMed1978

An analysis of the dose-response relationship at voltage-clamped frog neuromuscular junctions.

1. Frog neuromuscular junctions were viewed with Nomarski optics and voltage clamped. Agonist was applied ionophoretically and agonist concentrations were measured using a micro-electrode sensitive to quaternary amines. 2. The dose-response relationship was studied using the agonists carbamylcholine, suberyldicholine and hydroxyphenyl-propyltrimethylammonium. 3. With all of these agonists, it appeared that the ACh receptor could be active when either one or two agonist binding sites were occupied. The receptor was much more likely to be active when both sites were occupied. Agonist dissociation constants and receptor activation probabilities were estimated by non-linear regression techniques for several possible receptor activation schemes.

Animals↗

PubMed2001

Alterations in transmission, vesicle dynamics, and transmitter release machinery at NCAM-deficient neuromuscular junctions.

Although functional neuromuscular junctions (NMJs) form in NCAM-deficient mice, they exhibit multiple alterations in presynaptic organization and function. Profound depression and unusual periodic total transmission failures with repetitive stimulation point to a defect in vesicle mobilization/cycling, and these defects were mimicked in (+/+) NMJs by inhibitors of myosin light chain kinase, known to affect vesicle mobilization. Two separate release mechanisms, utilizing different endocytic machinery and Ca(2+) channels, were shown to coexist in (-/-) terminals, with the mature process targeted to presynaptic membrane opposed to muscle, and an abnormally retained immature process targeted to the remainder of the presynaptic terminal and axon. Thus, NCAM plays a critical and heretofore unsuspected role in the molecular organization of the presynaptic NMJ.

Animals↗