Effect of Lambert‐Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse

Waterman, Sally A.; Lang, Bethan; Newsom‐Davis, John

doi:10.1002/ana.410420204

Cited by 105 publications

(51 citation statements)

References 44 publications

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“…Taken in conjunction with these published studies, our data provide strong evidence that antibodies directed against P͞Q-type VDCCs are responsible for the impairment of neuromuscular transmission in LEMS. These (1998) findings also are consistent with the study of Waterman et al (26) in which passive transfer of LEMS IgG blocked the component of neurotransmitter release subserved by both P-type and Q-type VDCCs in the autonomic neurons of mice. No inhibition of calcium influx was observed in the ␣ 1B (G1A1) cell line with IgGs from any of the six LEMS patients tested.…”

Section: Discussionsupporting

confidence: 87%

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Pinto

Gillard²,

Moss³

et al. 1998

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

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112

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The pharmacological properties of voltagedependent calcium channel (VDCC) subtypes appear mainly to be determined by the ␣ 1 pore-forming subunit but, whether P-and Q-type VDCCs are encoded by the same ␣ 1 gene presently is unresolved. To investigate this, we used IgG antibodies to presynaptic VDCCs at motor nerve terminals that underlie muscle weakness in the autoimmune LambertEaton myasthenic syndrome (LEMS). We first studied their action on changes in intracellular free Ca 2؉ concentration [Ca 2؉ ] i in human embryonic kidney (HEK293) cell lines expressing different combinations of human recombinant VDCC subunits. Incubation for 18 h with LEMS IgG (2 mg͞ml) caused a significant dose-dependent reduction in the K ؉ -stimulated [Ca 2؉ ] i increase in the ␣ 1A cell line but not in the ␣ 1B , ␣ 1C , ␣ 1D , and ␣ 1E cell lines, establishing the ␣ 1A subunit as the target for these autoantibodies. Exploiting this specificity, we incubated cultured rat cerebellar neurones with LEMS IgG and observed a reduction in P-type current in Purkinje cells and both P-and Q-type currents in granule cells. These data are consistent with the hypothesis that the ␣ 1A gene encodes for the pore-forming subunit of both P-type and Q-type VDCCs.

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Section: Discussionsupporting

confidence: 87%

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Pinto

Gillard²,

Moss³

et al. 1998

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

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112

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“…1,6 The return of pupillary light reflexes following administration of 3,4-diaminopyridine and pyridostigmine in our patient confirms the hypothesis that the pathophysiological mechanism of autonomic dysfunction in LEMS is similar to that of the muscle weakness and relates to antibodymediated inhibition of neurotransmitter release in cholinergic autonomic synapses. 3,7 Furthermore, it is consistent with reports of improvement of autonomic symptoms with 3,4-diaminopyridine.…”

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confidence: 79%

Erratum

2001

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“…[77] P/Qtype VGCCs are also present at autonomic synapses explaining the frequent autonomic involvement in these patients. [78] …”

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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Effect of Lambert‐Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse

Cited by 105 publications

References 44 publications

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Erratum

Autoimmune disorders of the neuromuscular junction

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Effect of Lambert‐Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse

Cited by 105 publications

References 44 publications

Human autoantibodies specific for the α 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Erratum

Autoimmune disorders of the neuromuscular junction

Contact Info

Product

Resources

About

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

Human autoantibodies specific for the α _1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons