Quantal Components of End‐plate Potentials in the Myasthenic Syndrome*

Lambert, Edward H.; Elmqvist, D.

doi:10.1111/j.1749-6632.1971.tb30750.x

Cited by 287 publications

(126 citation statements)

References 26 publications

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“…Since the first descriptions of LES as a neuromuscular disorder (Anderson et al, 1953;Lambert et al, 1956;Eaton and Lambert, 1957), a number of reports have provided evidence that the disease results from the production of autoantibodies that act on the presynaptic terminal (Elmqvist and Lambert, 1968;Lambert and Elmqvist, 1971;Cull-Candy et al, 1980;Kim, 1986). The hypothesis that neuromuscular weakness results from decreased Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…Lambert-Eaton myasthenic syndrome (LES) is an autoimmune disorder characterized by decreased neurotransmitter release at the neuromuscular junction (Elmqvist and Lambert, 1968;Lambert and Elmqvist, 1971). Ultrastructural analysis has revealed that motoneurons from LES patients have fewer active zones, which are less well organized, and contain fewer active zone particles (Fukunaga et al, 1982).…”

mentioning

confidence: 99%

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Reduction of Calcium Currents by Lambert–Eaton Syndrome Sera: Motoneurons Are Preferentially Affected, and L-Type Currents Are Spared

García

Beam

1996

J. Neurosci.

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Previous work has demonstrated that Lambert-Eaton syndrome (LES) antibodies reduce calcium currents in nonneuronal cells and sensory neurons and reduce the amplitude of extracellularly recorded currents at mouse motor nerve terminals. We compared effects of LES sera on whole-cell currents of cultured nerve and muscle. LES sera more strongly reduced calcium currents in motoneurons than in sensory neurons. Motoneuronal potassium currents were unaffected. The sera minimally affected calcium currents in skeletal and cardiac muscle. In motoneurons, both low voltage-activated (LVA) and high voltage-activated (HVA) components of calcium current were decreased, demonstrating that the sera targeted more than one calcium channel type. The HVA current remaining in LES-treated motoneurons was little affected by micromolar -conotoxin MVIIC but was reduced Ͼ70% by micromolar nimodipine. This pharmacological profile contrasts with untreated cells and suggests that LES sera primarily spare L-type currents in motoneurons.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reduction of Calcium Currents by Lambert–Eaton Syndrome Sera: Motoneurons Are Preferentially Affected, and L-Type Currents Are Spared

García

Beam

1996

J. Neurosci.

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“…The EPPS are very small, as they are in MG, but the MEPPS are of normal amplitude. [67] In these classic studies, repetitive stimulation of the nerve showed that the endplate potential increased during repetitive stimulation and also when extracellular calcium was raised. These results suggested a possible defect in the presynaptic voltage-gated calcium channels (VGCC).…”

Section: Mechanisms Of Diseasementioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

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“…Lambert-Eaton myasthenic syndrome (LES) is a human autoimmune disorder characterized by autonomic dysfunction and muscle weakness resulting from reduced neurotransmitter release (1,2). At neuromuscular junctions, transmitter release occurs at discrete sites called active zones (3,4).…”

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confidence: 99%

Lambert-Eaton sera reduce low-voltage and high-voltage activated Ca2+ currents in murine dorsal root ganglion neurons.

García

Mynlieff²,

Sanders³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-gated Ca2+ channels are categorized as either high-voltage activated (HVA) or low-voltage activated (LVA), and a subtype (or subtypes) of HVA Ca2+ channels link the presynaptic depolarization to rapid neurotransmitter release. Reductions in transmitter release are characteristic of the autoimmune disorder, Lambert-Eaton syndrome (LES). Because antibodies from LES patients reduce Ca2+ influx in a variety of cell types and disrupt the intramembrane organization of active zones at neuromuscular synapses, specificity of LES antibodies for the Ca2+ channels that control transmitter release has been suggested as the mechanism for disease. We tested sera from four patients with LES. Serum samples from three of the four patients reduced both the maximal LVA and HVA Ca2+ conductances in murine dorsal root ganglion neurons. Thus, even though LES is expressed as a neuromuscular and autonomic disorder, our studies suggest that Ca2+ channels may be broadly affected in LES patients. To account for the specificity of disease expression, we suggest that incapacitation of only a fraction of the Ca2+ channels clustered at active zones would severely depress transmitter release. In particular, if several Ca2+ channels in a cluster are normally required to open simultaneously before transmitter release becomes likely, the loss of a few active zone Ca2+ channels would exponentially reduce the probability of transmitter release. This model may explain why LES is expressed as a neuromuscular disorder and can account for a clinical hallmark of LES, facilitation of neuromuscular transmission produced by vigorous voluntary effort.Lambert-Eaton myasthenic syndrome (LES) is a human autoimmune disorder characterized by autonomic dysfunction and muscle weakness resulting from reduced neurotransmitter release (1, 2). At neuromuscular junctions, transmitter release occurs at discrete sites called active zones (3, 4). In freezefracture views of neuromuscular synapses, intramembrane particles, which are thought to include Ca2+ channels, are organized in linear arrays at active zones (5-7). The hypothesis that LES antibodies target the Ca2+ channels that control transmitter release arose from the observation that LES antibodies decrease the number of active zones and disrupt active zone organization in mice and humans (8-10). Further support for this hypothesis has been based on the demonstration that LES antibodies decrease Ca2+ influx in transformed cells such as small cell lung carcinoma (11, 12), rat (13) and human (14) MATERIALS AND METHODS Serum Preparation. Serum obtained from four LES patients was dialyzed (exclusion of .100 kDa) for 24 hr against culture medium at a sample-to-dialysate ratio of approximately 1:100, with one dialysate change at about 8 hr (12). Initial experiments for Patient One used whole serum without dialysis; because no obvious differences were observed between whole and dialyzed serum, the results for this patient were pooled and averaged. Serum was added to the culture medium at approximately 1:20 ...

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Quantal Components of End‐plate Potentials in the Myasthenic Syndrome*

Cited by 287 publications

References 26 publications

Reduction of Calcium Currents by Lambert–Eaton Syndrome Sera: Motoneurons Are Preferentially Affected, and L-Type Currents Are Spared

Reduction of Calcium Currents by Lambert–Eaton Syndrome Sera: Motoneurons Are Preferentially Affected, and L-Type Currents Are Spared

Autoimmune disorders of the neuromuscular junction

Lambert-Eaton sera reduce low-voltage and high-voltage activated Ca2+ currents in murine dorsal root ganglion neurons.

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