Syntrophin Isoforms at the Neuromuscular Junction: Developmental Time Course and Differential Localization

Kramarcy, Neal R.; Sealock, Robert

doi:10.1006/mcne.1999.0823

Cited by 51 publications

(56 citation statements)

References 64 publications

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“…However, these antibodies did not distinguish between the known isoforms of these proteins. Previous studies, using isoformspecific antibodies for Na V 1 and syntrophins, suggest that in newborn muscles the isoforms characteristic of the adult NMJ (Na V 1.4, ␤ 2 -syntrophin) are present in very low amounts, if at all (Lupa et al, 1993;Kramarcy and Sealock, 2000). Therefore, we believe that the major isoforms of these proteins that we have detected in newborn muscles are Na V 1.5 and ␣-syntrophin.…”

Section: Discussionsupporting

confidence: 56%

“…Our findings that syntrophin is already concentrated at the NMJ before birth and does not have the same membrane distribution as ankyrinG or Na V 1 during the first 2 weeks after birth suggests that syntrophins are unlikely to play a role in initiating Na V 1 accumulation at the NMJ. However, we cannot exclude the possibility that syntrophins (presumably ␣-syntrophin) (Kramarcy and Sealock, 2000) could help to stabilize ankyrinG-Na V 1 interactions at mature NMJs.…”

Section: Stabilization Of Na V 1 Clusters At Maturing Nmjsmentioning

confidence: 98%

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Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats

et al. 2003

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Spatial segregation of membrane proteins is a feature of many excitable cells. In skeletal muscle, clusters of acetylcholine receptors (AChRs) and voltage-gated sodium channels (Na V 1s) occupy distinct domains at the neuromuscular junction (NMJ). We used quantitative immunolabeling of developing rat soleus muscles to study the mechanism of ion channel segregation and Na V 1 clustering at NMJs. When Na V 1s can first be detected, at birth, they already occupy a postsynaptic domain that is distinct from that occupied by AChRs. At this time, Na V 1s are expressed only in a diffuse area that extends 50 -100 m from the immature NMJ. However, in the region of the high-density AChR cluster at NMJ itself, Na V 1s are actually present in lower density than in the immediately surrounding membrane. These distinctive features of the Na V 1 distribution at birth are closely correlated with the distribution of ankyrinG immunolabeling. This suggests that an interaction with ankyrinG plays a role in the initial segregation of Na V 1s from AChRs. Both Na V 1 and ankyrinG become clustered at the NMJ itself 1-2 weeks after birth, coincident with the formation of postsynaptic folds. Syntrophin immunolabeling codistributes with AChRs and never resembles that for Na V 1 or ankyrinG. Therefore, syntrophin is unlikely to play an important part in the initial accumulation of Na V 1 at the NMJ. These findings suggest that the segregation of Na V 1 from AChRs begins early in NMJ formation and occurs as a result of the physical exclusion of Na V 1 and ankyrinG from the region of nerve-muscle contact rather than by a process of active clustering.

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Section: Discussionsupporting

confidence: 56%

Section: Stabilization Of Na V 1 Clusters At Maturing Nmjsmentioning

confidence: 98%

Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats

et al. 2003

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“…Because ␤2-syntrophin has Ͼ43% amino acid identity to ␣-syntrophin and is highly localized at the NMJ postsynaptic membrane where, like ␣-syntrophin, it is present both at the AChR-rich crest and in the junctional folds (Peters et al, 1994;Kramarcy and Sealock, 2000), we hypothesized that this isoform may compensate to some extent for the loss of ␣-syntrophin. To examine this possibility, we used gene disruption technology to generate mice lacking ␤2-syntrophin (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, cells often express more than one syntrophin isoform. In skeletal muscle, four of the five syntrophin isoforms (␣, ␤1, ␤2, ␥2) are expressed (Adams et al, 1993;Ahn et al, 1994;Piluso et al, 2000), with both ␣-and ␤2-syntrophin present at the postsynaptic neuromuscular junction (NMJ) (Peters et al, 1994;Kramarcy and Sealock, 2000).…”

Section: Introductionmentioning

confidence: 99%

Structural Abnormalities at Neuromuscular Synapses Lacking Multiple Syntrophin Isoforms

Adams¹,

Kramarcy²,

Fukuda³

et al. 2004

J. Neurosci.

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The syntrophins are modular adapter proteins that function by recruiting signaling molecules to the cytoskeleton via their direct association with proteins of the dystrophin protein family. We investigated the physiological function of ␤2-syntrophin by generating a line of mice lacking this syntrophin isoform. The ␤2-syntrophin null mice show no overt phenotype, or muscular dystrophy, and form structurally normal neuromuscular junctions (NMJs). To determine whether physiological consequences caused by the lack of ␤2-syntrophin were masked by compensation from the ␣-syntrophin isoform, we crossed these mice with our previously described ␣-syntrophin null mice to produce mice lacking both isoforms. The ␣/␤2-syntrophin null mice have NMJs that are structurally more aberrant than those lacking only ␣-syntrophin. The NMJs of the ␣/␤2-syntrophin null mice have fewer junctional folds than either parent strain, and the remaining folds are abnormally shaped with few openings to the synaptic space. The levels of acetylcholine receptors are reduced to 23% of wild type in mice lacking both syntrophin isoforms. Furthermore, the ␣/␤2-syntrophin null mice ran significantly shorter distances on voluntary exercise wheels despite having normal neuromuscular junction transmission as determined by microelectrode recording of endplate potentials. We conclude that both ␣-syntrophin and ␤2-syntrophin play distinct roles in forming and maintaining NMJ structure and that each syntrophin can partially compensate for the loss of the other.

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“…64 In addition, the skeletal muscle γ 2 -syntrophin was found at high levels only at the postsynaptic membrane of the neuromuscular junctions. 65,66 Alsoγ 2 -syntrophin has been detected in skeletal muscle, where it has been reported to localize to the sarcolemma 55 and to be able to bind the C-terminus of Nav1.5 through its PDZ domain, regulating the gating properties of the sodium channel. 67 In addition to syntrophin, other scaffolding proteins such as caveolin-3 (CAV3), which is present in the caveolae, flask-shaped plasma membrane microdomains, are involved in signal transduction and vesicle trafficking in myocytes, modulating cardiac remodeling during heart failure.…”

Section: Dystrophin the Dgc And Ion Channelsmentioning

confidence: 99%

Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle

Vatta

Faulkner

2006

Future Cardiol.

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SummaryThe heart is a force-generating organ that responds to self-generated electrical stimuli from specialized cardiomyocytes. This function is modulated by sympathetic and parasympathetic activity.In order to contract and accommodate the repetitive morphological changes induced by the cardiac cycle, cardiomyocytes depend on their highly evolved and specialized cytoskeletal apparatus. Defects in components of the cytoskeleton, in the long term, affect the ability of the cell to compensate at both functional and structural levels. In addition to the structural remodeling, the myocardium becomes increasingly susceptible to altered electrical activity leading to arrhythmogenesis. The development of arrhythmias secondary to structural remodeling defects has been noted, although the detailed molecular mechanisms are still elusive. Here I will review the current knowledge of the molecular and functional relationships between the cytoskeleton and ion channels and, I will discuss the future impact of new data on molecular cardiology research and clinical practice.

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Syntrophin Isoforms at the Neuromuscular Junction: Developmental Time Course and Differential Localization

Cited by 51 publications

References 64 publications

Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats

Voltage-Gated Sodium Channels and AnkyrinG Occupy a Different Postsynaptic Domain from Acetylcholine Receptors from an Early Stage of Neuromuscular Junction Maturation in Rats

Structural Abnormalities at Neuromuscular Synapses Lacking Multiple Syntrophin Isoforms

Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle

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