Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line

Roberts, Andrew; Perera, Shiromi M.; Lang, Bethan; Vincent, Angela; Newsom‐Davis, John

doi:10.1038/317737a0

Cited by 242 publications

(114 citation statements)

References 12 publications

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“…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)(9)(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) neuroblastoma, and rat thyroid cells (15), as well as in secretory cells such as adrenal chromaffin (16)(17)(18) and rat pituitary cells (19). It is uncertain that these cells, which are either transformed or involved in hormonal secretion, express the same kinds of Ca2+ channels that are contained in normal neurons (20).…”

mentioning

confidence: 93%

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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mentioning

confidence: 93%

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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“…In LEMS, a second PND involving the NMJ, patients harbor antibodies against components of the presynaptic motor endplate, and 60% of LEMS patients are found to have small cell lung cancer. In vitro, LEMS antibodies lead to impaired calcium flux (24,25) and impaired acetylcholine release (26) from the presynaptic motor neuron. Unlike MG, a single autoantigen has not been identified in LEMS.…”

Section: Classification Of the Pndsmentioning

confidence: 99%

Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain.

Darnell

1996

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

253

132

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Paraneoplastic neurologic disorders (PNDs) are believed to be autoimmune neuronal degenerations that develop in some patients with systemic cancer. A series of genes encoding previously undiscovered neuronal proteins have been cloned using antiserum from PND patients. Identification of these onconeural antigens suggests a reclassification of the disorders into four groups: those in which neuromuscular junction proteins, nerve terminal/vesicleassociated proteins, neuronal RNA binding proteins, or neuronal signal-transduction proteins serve as target antigens. This review considers insights into basic neurobiology, tumor immunology, and autoimmune neuronal degeneration offered by the characterization of the onconeural antigens.

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“…To test this hypothesis, the effects of LES antibodies on radiocalcium fluxes or calcium currents have been examined in a number of systems. The antibodies reduce calcium influx in small-cell lung carcinoma (Roberts et al, 1985), rat anterior pituitary (Login et al, 1987), adrenal chromaffin (Kim and Neher, 1988;Viglione et al, 1992), neuroblastoma (Peers et al, 1990;Grassi et al, 1994), rat thyroid cell line and dorsal root ganglion (DRG) cells (García et al, 1996). Recently, it has been shown that LES antibodies decrease mixed sodium and calcium currents at the nerve terminals of mice (Smith et al, 1995).…”

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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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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Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line

Cited by 242 publications

References 12 publications

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

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

Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain.

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

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