Clustering of sodium channels at the neuromuscular junction

Caldwell, John H.

doi:10.1002/(sici)1097-0029(20000401)49:1<84::aid-jemt9>3.0.co;2-e

Cited by 42 publications

(26 citation statements)

References 45 publications

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“…In muscle, syncoilin expression is enriched at the neuromuscular junction (Newey et al, 2001), and many morphological and molecular similarities exist between nodes of Ranvier and neuromuscular junctions (Caldwell, 2000;Ellisman, 1979). Several proteins including N-cadherin (Cifuentes-Diaz et al, 1994), N-CAM and cytotactin (Rieger et al, 1986) are expressed or enriched at both the neuromuscular junction and node of Ranvier and function in cell-cell adhesion, neurite outgrowth and synaptic plasticity.…”

Section: Discussionsupporting

confidence: 90%

Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons

Clarke

Edwards

McCullagh

et al. 2010

Journal of Cell Science

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SummarySyncoilin is an atypical type III intermediate filament (IF) protein, which is expressed in muscle and is associated with the dystrophinassociated protein complex. Here, we show that syncoilin is expressed in both the central and peripheral nervous systems. Isoform Sync1 is dominant in the brain, but isoform Sync2 is dominant in the spinal cord and sciatic nerve. Peripherin is a type III IF protein that has been shown to colocalise and interact with syncoilin. Our analyses suggest that syncoilin might function to modulate formation of peripherin filament networks through binding to peripherin isoforms. Peripherin is associated with the disease amyotrophic lateral sclerosis (ALS), thus establishing a link between syncoilin and ALS. A neuronal analysis of the syncoilin-null mouse (Sync -/-) revealed a reduced ability in accelerating treadmill and rotarod tests. This phenotype might be attributable to the impaired function of extensor digitorum longus muscle and type IIb fibres caused by a shift from large-to small-calibre motor axons in the ventral root.

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Section: Discussionsupporting

confidence: 90%

Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons

Clarke

Edwards

McCullagh

et al. 2010

Journal of Cell Science

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“…A relatively small hyperpolarization in this voltage range redistributes sodium channels from the inactive to available state. Sodium channels are concentrated near nAChRs at the postsynaptic NMJ where their density is 20-fold that of extrajunctional sarcolemma (32). This clustering insures efficient neuromuscular transmission (67).…”

Section: Discussionmentioning

confidence: 99%

“…Because this distance is 2-3 times the length constant of diaphragm muscle, it indicates that the measured hyperpolarization must originate from extrajunctional nAChRs and Na,K-ATPase. Although less dense than at the NMJ, nAChRs are present on extrajunctional sarcolemma at about 40 per m 2 (32). Other studies have shown that the low levels of ACh resulting from non-quantal release (ϳ50 nM) at the NMJ hyperpolarize the junctional membrane by approximately Ϫ3 mV by a mechanism that involves stimulation of the Na,K-ATPase (6, 7).…”

Section: The Functional Interaction Between the Nachr And The Nak-atmentioning

confidence: 99%

The Nicotinic Acetylcholine Receptor and the Na,K-ATPase α2 Isoform Interact to Regulate Membrane Electrogenesis in Skeletal Muscle

Heiny

Кравцова

Mandel

et al. 2010

Journal of Biological Chemistry

116

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The interaction operates at the neuromuscular junction as well as on extrajunctional sarcolemma. The Na,K-ATPase ␣2 isozyme is enriched at the postsynaptic neuromuscular junction and co-localizes with nAChRs. The nAChR and Na,K-ATPase ␣ subunits specifically coimmunoprecipitate with each other, phospholemman, and caveolin-3. In a purified membrane preparation from Torpedo californica enriched in nAChRs and the Na,K-ATPase, a ouabain-induced conformational change of the Na,K-ATPase enhances a conformational transition of the nAChR to a desensitized state. These results suggest a mechanism by which the nAChR in a desensitized state with high apparent affinity for agonist interacts with the Na,K-ATPase to stimulate active transport. The interaction utilizes a membranedelimited complex involving protein-protein interactions, either directly or through additional protein partners. This interaction is expected to enhance neuromuscular transmission and muscle excitation. The nicotinic acetylcholine receptor (nAChR)2 and the Na,K-ATPase are integral membrane proteins that play key roles in membrane excitation. We previously identified a regulatory mechanism, termed acetylcholine (ACh)-induced hyperpolarization, whereby the nAChR and the Na,K-ATPase functionally interact to modulate the membrane potential of rat skeletal muscle (1-4). In this interaction, the binding of nanomolar concentrations of ACh to the nAChR stimulates electrogenic transport by the Na,K-ATPase ␣2 isozyme, causing a membrane hyperpolarization of about Ϫ4 mV. This effect requires prolonged exposure to nanomolar concentrations of nicotinic agonist. This property distinguishes it from the more well characterized, rapid action of micromolar concentrations of ACh, which open the nAChR and produce membrane depolarization (5). This finding suggested that a non-conducting conformation of the nAChR, rather than the open state, is involved in signaling to the Na,K-ATPase. In addition, it was shown that the nAChR and Na,K-ATPase can reciprocally interact in a membrane preparation from the Torpedo electric organ (1), a muscle-derived tissue that is rich in muscle nAChRs and Na,K-ATPase. This finding suggested that the nAChR and Na,K-ATPase may interact as part of a membrane-associated regulatory complex.Importantly, this regulation of Na,K-ATPase activity by the nAChR operates under the physiological conditions of normal muscle use. Its ACh concentration dependence is in the range of the residual ACh concentrations that remain in the muscle interstitial spaces for some time following nerve excitation, and to the ACh concentrations that arise at the neuromuscular junction (NMJ) from non-quantal ACh release. The later have also been shown to activate the Na,K-ATPase and hyperpolarize the end plate membrane (6, 7). Notably, this hyperpolariza-* This work was supported, in whole or in part, by National Institutes of Health

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“…These electrical field stimulation-induced twitches could not be inhibited by d-tubocurarine, indicating that tetrodotoxin at this concentration not only blocks neural transmission but also directly inhibits the striated muscle contraction. Voltage-dependent sodium channels are distributed with different densities over the entire muscle cell membrane at least in skeletal muscles [2,3] and might reflect the sensitivity of esophageal striated muscle fibers to tetrodotoxin.…”

Section: Discussionmentioning

confidence: 99%

Key Role of Mucosal Primary Afferents in Mediating the Inhibitory Influence of Capsaicin on Vagally Mediated Contractions in the Mouse Esophagus

Boudaka

Wörl

Shiina

et al. 2007

The Journal of Veterinary Medical Science

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ABSTRACT. Transient receptor potential ion channel of the vanilloid type 1 (TRPV1)-dependent pathway, consisting of capsaicin-sensitive tachykininergic primary afferent and myenteric nitrergic neurons, was suggested to mediate the inhibitory effect of capsaicin on the vagally mediated striated muscle contractions in the rat esophagus. These primary afferent neurons upon entering into the esophagus are distributed through the myenteric plexus, terminating either in the myenteric ganglia or en route to the mucosa where they branch into a delicate net of fine varicose fibers. Therefore, this study aimed to investigate whether the mucosal primary afferents are a main mediator for the capsaicin inhibitory influence on vagally mediated contractions in the mouse esophagus. For this purpose, the vagally induced contractile activity of a thoracic esophageal segment was measured in the circular direction with a force transducer. Vagal stimulation (30 µsec, 25 V, 1-50 Hz for 1 sec) produced monophasic contractile responses, whose amplitudes were frequency-dependent. These contractions were completely abolished by d-tubocurarine (5 µM) while resistant to atropine (1 µM) and hexamethonium (100 µM). Capsaicin (30 µM) significantly inhibited the vagally induced contractions in esophagi with intact mucosa while its effect on preparations without mucosa was insignificant. Additionally, immunocytochemistry revealed the presence of TRPV1-positive nerve fibers in the tunica mucosa. Taken together, we conclude that in the mouse esophagus, capsaicin inhibits the vagally mediated striated muscle contractions mainly through its action on mucosal primary afferents, which in turn activate the presumed inhibitory local reflex arc. KEY WORDS: capsaicin-sensitive neurons, enteric co-innervation, local effector function, TRPV1, vagus nerve.J. Vet. Med. Sci. 69(4): 365-372, 2007 A peripheral reflex arc composed of capsaicin-sensitive tachykininergic primary afferent and myenteric nitrergic neurons have been shown to negatively influence the vagally mediated striated muscle contractions in the rat esophagus [27]. Esophageal neuromuscular junctions receive a dual innervation from both vagal nerve fibers originating in the brain stem and from varicose enteric nerve fibers originating in the myenteric plexus, the so-called enteric co-innervation [for review see 21, 34]. Enteric neurons in the esophagus are contacted by primary afferents of spinal and vagal origin [19,20,25]. A substantial number of these primary afferents, mainly of spinal origin, were shown to be immunoreactive to the transient receptor potential ion channel of the vanilloid type 1 (TRPV1) and called capsaicin-sensitive sensory neurons [12,14,15,23,30,31,33]. These neurons can modulate intestinal motility by transferring signals from the gastrointestinal tract to the central nervous system and simultaneously releasing transmitters, in particular substance P (SP) and calcitonin generelated peptide (CGRP) that can influence the activity of intrinsic neurons [14,16].Primary affe...

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Clustering of sodium channels at the neuromuscular junction

Cited by 42 publications

References 45 publications

Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons

Syncoilin modulates peripherin filament networks and is necessary for large-calibre motor neurons

The Nicotinic Acetylcholine Receptor and the Na,K-ATPase α2 Isoform Interact to Regulate Membrane Electrogenesis in Skeletal Muscle

Key Role of Mucosal Primary Afferents in Mediating the Inhibitory Influence of Capsaicin on Vagally Mediated Contractions in the Mouse Esophagus

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