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

Pinto, Ashwin; Gillard, Samantha; Moss, Fiona; Whyte, Kathryn A; Brust, Paul F.; Williams, Mark E.; Stauderman, Ken; Harpold, Michael M.; Lang, Bethan; Newsom‐Davis, John; Bleakman, David; Lodge, David; Boot, John R.

doi:10.1073/pnas.95.14.8328

Cited by 112 publications

(82 citation statements)

References 40 publications

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“…[75] SCLCs express VGCCs on their surface, and LEMS IgG reduces the numbers of VGCC in these cells and in other cell lines expressing the calcium channels. [76] Just as AChR synthesis is increased in MG muscle, so also there is likely to be increased synthesis of P/Q-type VGCC or alternative channels in motor nerves in LEMS. [77] P/Qtype VGCCs are also present at autonomic synapses explaining the frequent autonomic involvement in these patients.…”

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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Section: Mechanisms Of Diseasementioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

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“…PCA patients have a high titer of anti-VGCC antibody (14)(15)(16)(17) and undergo a selective loss of P/Q-type VGCC-containing cerebellar neurons (2,18). Sera from LEMS patients, known to contain anti-VGCC antibodies, reduce P/Q-type VGCC surface expression in cerebellar granule and Purkinje neurons (19), consistent with an overlap of clinical syndromes between LEMS and PCA and, possibly, of pathogenic mechanism. There is no evidence to date that passive transfer of sera from LEMS or PCA patients is sufficient to cause central nervous system disease.…”

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confidence: 81%

Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo

Liao

Safa²,

Chen³

et al. 2008

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

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Voltage-gated Ca 2؉ channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.Lambert-Eaton myasthenic syndrome ͉ paraneoplastic ͉ P/Q-type ͉ N-type ͉ neurotransmission T he association between anti-voltage-gated Ca 2ϩ channel (VGCC) antibody and paraneoplastic cerebellar ataxia (PCA) dates back several decades to clinical observations of the coexistence of small-cell lung cancer with either cerebellar ataxia, Lambert-Eaton myasthenic syndrome (LEMS), or both (1, 2). The majority of these cancer patients with neurological symptoms have antibody against different types of VGCCs, especially P/Q-and N-type (3-5). The presence of different antibodies may be the consequence of an autoimmune response against the cancer cells (6, 7), known to express different VGCCs (8). There is conclusive evidence that the peripheral disease LEMS is caused by anti-VGCC antibodies, which diminish the availability of P/Q-type channels of the motor nerve terminals (9, 10).In contrast, much less is known about the origin of cerebellar ataxia associated with anti-VGCC antibody, although VGCCs are prominent in cerebellar neurons (11,12), and mutations in the P/Q-type VGCC cause ataxia (13). PCA patients have a high titer of anti-VGCC antibody (14-17) and undergo a selective loss of P/Q-type VGCC-containing cerebellar neurons (2, 18). Sera from LEMS patients, known to contain anti-VGCC antibodies, reduce P/Q-type VGCC surface expression in cerebellar granule and Purkinje neurons (19), consistent with an overlap of clinical syndromes between LEMS and PCA and, possibly, of pathogenic mechanism. There is no evidence to date that passive transfer of sera from LEMS or PCA patients is sufficient to cause central nervous system disease. Based on epitope mapping of antibody repertoire in patients with paraneoplastic neurological syndromes and small-cell lung cancer, we generated an antibody against a major epitope in the P/Q-type VGCC and evaluated its ability to affect cerebellar VGCC function and motor behavior. ResultsFunctional Effects of Anti-VGCC Antibody. We looked for...

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“…The underlying pathophysiology of LEMS is impaired calcium-dependent release of acetylcholine from motor nerve terminals (Elmqvist et al 1968). Circulating antibodies against voltage-gated calcium channels (VGCCs) are found in around 90% of LEMS patients (Lennon et al 1995;Motomura et al 1997) and result in the down-regulation of functional VGCCs (Pinto et al 1998). VGCCs are composed of a number of pharmacologically and electrophysiologically distinct subtypes.…”

Section: Lambert Eaton Myasthenic Syndromementioning

confidence: 99%

“…VGCCs are composed of a number of pharmacologically and electrophysiologically distinct subtypes. Although antibodies have been described that bind to the L-, N-and P-/Q-VGCC subtypes (Meriney et al 1996), only those directed against the P-/Q-subtype, which is responsible for pre-synaptic neurotransmitter release at the neuromuscular junction, have been shown to be pathogenic (Pinto et al 1998).…”

Section: Lambert Eaton Myasthenic Syndromementioning

confidence: 99%

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The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

Hubball

Martin

Lang

et al. 2009

Progress in Neurobiology

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Dysfunction of the gastrointestinal neuromuscular apparatus (including interstitial cells ofCajal) is presumed to underlie a heterogeneous group of disorders collectively termed gastrointestinal neuromuscular diseases (GINMDs). Humoral (antibody)-mediated autoimmunity directed against ligand-or voltage-gated ion channels or associated proteins involved in neuromuscular transmission is associated with several acquired neuromuscular diseases of the periphery and is now implicated in an increasing number of less well-characterised diseases. Anti-channel antibodies have been reported in small numbers of patients with GINMD, particularly in those with GI dysfunction secondary to an underlying disease such as neoplasia or infection. However, little is known of humoral autoimmunity in primary GINMDs.This thesis investigated the association between anti-channel antibodies and GINMD, and the human GI tract as a potential target of anti-channel antibodies. The presence of antivoltage-and ligand-gated antibodies was investigated in the serum of patients with primary achalasia, enteric dysmotility and intestinal pseudo-obstruction, and in those with GINMD secondary to Chagas' disease. The functional effect of sera from some of these patients on colonic smooth muscle contractility was also characterised. Finally, the distribution of six voltage-gated potassium channels (VGKCs), which serve essential roles in the peripheral and central nervous systems and are known targets of pathological autoantibodies, were investigated in all layers of the human GI tract.Our findings suggest that currently recognised anti-channel antibodies are not a common pathogenic factor in primary GINMDs. Anti-channel antibodies, in particular anti-VGKC antibodies, were however found in a significant number of individuals with Chagas' disease. Furthermore, circulating factors in patients with chagasic GI disease altered GI smooth muscle contractility in vitro which may have pathological relevance to GI

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

Cited by 112 publications

References 40 publications

Autoimmune disorders of the neuromuscular junction

Autoimmune disorders of the neuromuscular junction

Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

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

Cited by 112 publications

References 40 publications

Autoimmune disorders of the neuromuscular junction

Autoimmune disorders of the neuromuscular junction

Anti-Ca 2+ channel antibody attenuates Ca 2+ currents and mimics cerebellar ataxia in vivo

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

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

Anti-Ca ²⁺ channel antibody attenuates Ca ²⁺ currents and mimics cerebellar ataxia in vivo