Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

Giovannini, Federica; Sher, Emanuele; Webster, Richard; Boot, John R.; Lang, Bethan

doi:10.1038/sj.bjp.0704818

Cited by 54 publications

(35 citation statements)

References 65 publications

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“…Furthermore, Ca 2＋ influx via voltage-dependent Ca 2＋ channels is required for ACh-induced contraction in esophagus [23][24][25]. Therefore, our results also indicate that maintenance of a normal concentration of Ca 2＋ in extracellular fluid may be necessary for transmitter release upon nerve activation by EFS and for the triggering of an excitation-contraction coupling mechanism in esophageal smooth muscle [26].…”

Section: Discussionsupporting

confidence: 57%

MLCK and PKC Involvements via Gi and Rho A Protein in Contraction by the Electrical Field Stimulation in Feline Esophageal Smooth Muscle

Park

Shim

Kim

et al. 2010

Korean J Physiol Pharmacol

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W e have shown that myosin light chain kinase (MLCK) was required for the off-contraction in response to the electrical field stimulation (EFS) of feline esophageal smooth muscle. In this study, we investigated whether protein kinase C (PKC) may require the on-contraction in response to EFS using feline esophageal smooth muscle. The contractions were recorded using an isometric force transducer. On-contraction occurred in the presence of N G -nitro-L-arginine methyl ester (L-NAME), suggesting that nitric oxide acts as an inhibitory mediator in smooth muscle. The excitatory composition of both contractions was cholinergic dependent which was blocked by tetrodotoxin or atropine. The on-contraction was abolished in Ca 2＋ -free buffer but reappeared in normal Ca 2＋ -containing buffer indicating that the contraction was Ca 2＋ dependent. 4-aminopyridine (4-AP), voltage-dependent K＋ channel blocker, significantly enhanced on-contraction. Aluminum fluoride (a G-protein activator) increased on-contraction. Pertussis toxin (a Gi inactivator) and C3 exoenzyme (a rhoA inactivator) significantly decreased on-contraction suggesting that Gi or rhoA protein may be related with Ca 2＋ and K ＋ channel. ML-9, a MLCK inhibitor, significantly inhibited on-contraction, and chelerythrine (PKC inhibitor) affected on the contraction. These results suggest that endogenous cholinergic contractions activated directly by low-frequency EFS may be mediated by Ca 2＋ , and G proteins, such as Gi and rhoA, which resulted in the activation of MLCK, and PKC to produce the contraction in feline distal esophageal smooth muscle.

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Section: Discussionsupporting

confidence: 57%

MLCK and PKC Involvements via Gi and Rho A Protein in Contraction by the Electrical Field Stimulation in Feline Esophageal Smooth Muscle

Park

Shim

Kim

et al. 2010

Korean J Physiol Pharmacol

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“…[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. [78] …”

Section: Mechanisms Of Diseasementioning

confidence: 92%

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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“…Ca 2ϩ entry at the mature neuromuscular junction appears to occur primarily through P/Q Ca 2ϩ channels, because blocking these channels reduces the evoked release by Ͼ90% (Uchitel et al, 1992;Hong and Chang, 1995;Giovannini et al, 2002). However, a small portion of transmitter release persists (Hong and Chang, 1995;Giovannini et al, 2002) because of Ca 2ϩ current that is apparently carried by other Ca 2ϩ channel types (Lin and Lin-Shiau, 1997).…”

Section: Increased Probability Of Release In Low Camentioning

confidence: 99%

Decreased Synaptic Activity Shifts the Calcium Dependence of Release at the Mammalian Neuromuscular JunctionIn Vivo

Wang

Engisch²,

Li³

et al. 2004

J. Neurosci.

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We examined the mechanism underlying increased quantal content after block of activity at the mouse neuromuscular junction in vivo. We found that, when quantal content was measured in solution containing normal extracellular calcium, block of activity had no effect on either quantal content or the response to repetitive stimulation. However, when quantal content was measured in low extracellular calcium, there was a large increase in quantal content after block of activity. The increase in quantal content was accompanied by increased depression during repetitive stimulation. The explanation for these findings was that there was a shift in the calcium dependence of release after block of activity that manifested as an increase in probability of release in low extracellular calcium. Block of presynaptic P/Q channels eliminated the increase in probability of release. We propose that activity-dependent regulation of presynaptic calcium entry may contribute to homeostatic regulation of quantal content.

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Calcium channel subtypes contributing to acetylcholine release from normal, 4‐aminopyridine‐treated and myasthenic syndrome auto‐antibodies‐affected neuromuscular junctions

Cited by 54 publications

References 65 publications

MLCK and PKC Involvements via Gi and Rho A Protein in Contraction by the Electrical Field Stimulation in Feline Esophageal Smooth Muscle

MLCK and PKC Involvements via Gi and Rho A Protein in Contraction by the Electrical Field Stimulation in Feline Esophageal Smooth Muscle

Autoimmune disorders of the neuromuscular junction

Decreased Synaptic Activity Shifts the Calcium Dependence of Release at the Mammalian Neuromuscular JunctionIn Vivo

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