Snake venoms and the neuromuscular junction

There are approximately 420 venomous species of snakes living on the earth. Their venoms, each unique, can affect multiple organ systems. The venoms have a predilection for the peripheral nervous system where the neuromuscular junction is a favorite target. Those venoms affecting the release of acetylcholine from the presynaptic membrane are called beta-neurotoxins and those affecting the postsynaptic membrane are called alpha-neurotoxins. alpha-Bungarotoxin has been used in quantitative studies of acetylcholine receptor density and turnover and for the assay of antibodies directed against the acetylcholine receptor. A unique feature of timber rattlesnake venom is its ability to cause clinical myokymia. This likely results from a blockade of voltage gated K+ antibodies.     

Nerve,muscle, and neuromuscular junction electrophysiology at high temperature

Although the effect of low temperature on the peripheral nervous system has been systematically studied, the effect of high temperature has not. We investigated the effect of elevating limb temperature from 32°C to 42°C by performing sequential motor studies, antidromic sensory studies, and 3-Hz repetitive stimulation in normal subjects. In addition, we recorded single motor units by using threshold stimulation. On average, motor amplitude and duration decreased by 27% and 19%, respectively, whereas sensory amplitude and duration decreased by 50% and 26%, respectively. Neuromuscular transmission remained normal at 42°C. Single motor unit recordings revealed a reduction in amplitude of 26%, similar to the overall reduction in compound motor amplitude. These findings demonstrate that significant reductions in sensory and motor amplitudes can occur in normal nerves at high temperature; we hypothesize that these changes are secondary to alterations in nerve and muscle ion channel function. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 431–436, 1997     

Genetic defects and disorders at the neuromuscular junction

Genetic defects in molecules expressed at the neuromuscular junction (NMJ) cause congenital myasthenic syndromes (CMSs), which are characterized by muscle weakness, abnormal fatigability, amyotrophy, and minor facial anomalies. Muscle weakness mostly develops under 2 years but is also sometimes seen in adults. Mutations identified to date include (i) muscle nicotinic acetylcholine receptor (AChR) subunits, (ii) rapsyn that anchors and clusters AChRs at the neuromuscular junction, (iii) agrin that is released from the nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway, (iv) muscle-specific kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to rapsyn/AChR, (v) Dok-7 that transmits the AChR-clustering signal from agrin/LRP4/MuSK to rapsyn/AChR, (vi) skeletal muscle sodium channel type 1.4 (Nav1.4) that spreads the depolarization potential from the endplate throughout muscle fibers, (vii) collagen Q that anchors acetylcholinesterase to the synaptic basal lamina, and (viii) choline acetyltransferase that resynthesizes acetylcholine from recycled choline at the nerve terminal. In addition, mutations in the heparin sulfate proteoglycan perlecan, which binds to many molecules including collagen Q and dystroglycan, causes Schwartz-Jampel syndrome. Interestingly, mutations in LRP4 cause Cenani-Lenz syndactyly syndrome but not CMS. AChR, MuSK, and LRP4 are also targets of auto-antibodies in myasthenia gravis. In addition, molecules at the NMJ are targets of many other disease states AChRs are blocked by the snake toxin alpha-bungarotoxin and the plant poison curare. The presynaptic SNARE complex is attacked by botulinum toxin. Acetylcholinesterase is inhibited by the nerve gas sarin and by organophosphate pesticides. This review focuses on the molecular bases underlying defects of AChR, rapsyn, Nav1.4, collagen Q, and choline acetyltransferase.     

The neuromuscular junction: Anatomical features and adaptations to various forms of increased,or decreased neuromuscular activity

The neuromuscular junction (NMJ) allows communication between motor neurons and muscle fibers. During development, marked morphological changes occur as the functional NMJ is formed. During the postnatal period of rapid growth and muscle enlargement, endplate size concurrently increases. Even beyond this period of pronounced plasticity, the NMJ undergoes subtle morphological remodeling—expansion and retraction—although its overall dimensions remain stable. This natural, continual NMJ remodeling is amplified with alterations in neuromuscular activity. Increased activity, presented by exercise training, typically results in expansion of NMJ size. Disuse, brought about by neurotoxins, denervation, or spaceflight, also elicits substantial reconfiguring of the endplate.     

The neuromuscular junction: anatomical features and adaptations to various forms of increased, or decreased neuromuscular activity

The neuromuscular junction (NMJ) allows communication between motor neurons and muscle fibers. During development, marked morphological changes occur as the functional NMJ is formed. During the postnatal period of rapid growth and muscle enlargement, endplate size concurrently increases. Even beyond this period of pronounced plasticity, the NMJ undergoes subtle morphological remodeling--expansion and retraction--although its overall dimensions remain stable. This natural, continual NMJ remodeling is amplified with alterations in neuromuscular activity. Increased activity, presented by exercise training, typically results in expansion of NMJ size. Disuse, brought about by neurotoxins, denervation, or spaceflight, also elicits substantial reconfiguring of the endplate.     

Progress in perisynaptic Schwann cell and neuromuscular junction research

The neuromuscular junction(NMJ)is widely studied for its utility in investigating synaptic properties and processes and neuromuscular changes in response to injury,aging,and disease.The NMJ consists of three essential anatomic components,the pre-synaptic motor axon terminal,the post-synaptic nicotinic acetylcholine receptors(AchRs)on the muscle,and the perisynaptic Schwann cell(PSC),also known as the terminal Schwann cell,that caps the synapse(Figure 1A).     

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.     

Coated vesicle morphology and sub-populations at the neuromuscular junction

Serial sections of frog cutaneous pectoris neuromuscular junctions were examined to determine if isolated coated vesicles in one section are connected to infoldings of the presynaptic membrane in adjacent sections or are truly pinched off from the plasmalemma. Twenty percent of the coated vesicles examined serially were isolated from plasmalemma. In addition, two populations of coated vesicles were observed: those the size of synaptic vesicles and a smaller population (8% of total) of larger diameter (100 nm).     

Neuroendocrine lung tumors and disorders of the neuromuscular junction

We report four cases of Lambert-Eaton myasthenic syndrome (LEMS) or myasthenia gravis (MG) associated with pulmonary neuroendocrine carcinoma having prolonged survival. The tumors were atypical carcinoid or large cell neuroendocrine carcinoma. LEMS is associated with several neuroendocrine carcinomas. Because some neuroendocrine carcinomas have a better prognosis, aggressive tissue diagnosis of lung cancer in LEMS is warranted. Whether the association between MG and atypical carcinoid is a significant co-occurrence is uncertain.     

Immunology of the neuromuscular junction and presynaptic nerve terminal

The prevalence and incidence of myasthenia gravis is higher than previously thought. A potentially immunodominant T cell has been defined. The specific voltage-gated calcium channel subtype that is targeted by antibodies in the Lambert-Eaton myasthenic syndrome has been identified, and there is further evidence for the pathogenic role of autoantibodies in some cases of fetal arthrogryposis and in acquired neuromyotonia, Morvan's syndrome and Miller-Fisher syndrome.     

Barbiturates and transmitter release at the frog neuromuscular junction

The effects of the convulsant and anticonvulsant barbiturates, 5(2-cyclohexylidine ethyl)-5-ethyl barbituric acid (CHEB) an phenobarbital (PHB) were studied at the frog neuromuscular junction. Spontaneous transmitter liberation was augmented by both drugs irrespective of the external Ca2+ concentration, but CHEB was considerably more active than PHB. Miniature end plate potential amplitude was equally reduced by both drugs. The net effect of these agents on end plate potential (e.p.p.) amplitude varied depending on the external Ca2+ concentration. In Ca2+-deficient Ringer's solution both drugs increased the quantal content and the e.p.p. amplitude (CHEB more than PHB). In Ringer's solution containing a normal concentration of Ca2+ ions, both drugs depressed the evoked response and failed to alter the quantal content significantly.